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Objectives: Relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) often responds poorly to induction chemotherapy. However, recent research has shown a novel and effective drug treatment for R/R B-ALL. Methods: A total of eight patients with R/R B-ALL were enrolled in the study from November 2021 to August 2022. All patients received chemotherapy based on a combination regimen of venetoclax and azacitidine. The regimen was as follows venetoclax 100 mg d1, 200 mg d2, 400 mg d3–14, azacitidine 75 mg/m2 d1–7. Results: Five of eight patients achieved very deep and complete remission (CR) with minimal residual disease (MRD) less than 0.1%. One patient achieved partial remission. Two patients did not achieve remission. There were no serious adverse events and all patients were well tolerated. Three patients were eligible for consolidation chemotherapy and were bridged to CAR-T therapy. Conclusions: The combined regimen of venetoclax and azacitidine may be beneficial for patients with R/R B-ALL. [ABSTRACT FROM AUTHOR]

Objectives: The combination of Venetoclax (VEN) and Azacitidine (AZA) increases survival outcomes and yields excellent responses in patients with acute myeloid leukemia (AML). However, dose reduction (or discontinuation) is commonly encountered due to therapy-related toxicity. Thus, this study aimed to investigate the efficiency and safety of a lower dosage of venetoclax for the treatment of AML. Methods: This observational study analyzed the characteristics and outcomes of newly diagnosed AML patients who received 100 mg VEN combined with AZA for 14 days at our institution. Results: A total of 36 patients were enrolled, and the median age at diagnosis was 64 years. After a median follow-up of 15 (range 4–29) months, the median overall survival (OS) and progression-free survival (PFS) for the whole cohort were 17 (4–29) months and 12 (1–28) months, respectively. Meanwhile, the overall response rate (ORR) was 69.4%, and the CRc rate was 66.7% in the whole cohort. Subgroup analysis revealed that NPM1 mutations and FAB-M5 subtype were associated with higher response rates, whereas the adverse ELN risk group was predictive of an inferior response. Moreover, ASXL1, NPM1, and IDH1/2 mutations negatively impacted PFS. Discussion: Our study optimized the administration of venetoclax plus azacytidine for the treatment of AML patients. Response rates were favorable, with median survival in agreement with the findings of earlier reports, offering valuable insights for optimizing VEN-based regimens. Conclusion: In summary, the VEN combination regimen is effective for the treatment of newly diagnosed AML patients in the real world despite VEN dose reductions. [ABSTRACT FROM AUTHOR]

Myeloid leukemia is a stem cell disease with high mortality due to the challenges of high-dose treatments and side effects. Innovative nanoparticle drug delivery systems are being explored to enhance efficacy and tissue-targeted therapy. This study investigates the potential of Bentonite (BNT)-based nanoparticles (NPs) as drug carriers for azacitidine (AZA) in treating THP-1 and K562 myeloid leukemia (AML) cell lines, aiming to improve drug stability, bioavailability, and therapeutic efficacy while ensuring controlled release. Material and Method: Bentonite clay morphology was analyzed using Scanning Electron Microscopes. The BNT-AZA combination was tested in THP-1 and K562 cell cultures via in vitro proliferation tests, CCK-8 assays, and drug release tests with dialysis membranes. Apoptosis and internalization were evaluated using Annexin V-FITC and fluorescence methods, respectively. Results: The BNT-AZA exhibited controlled release over 8 hours, with 50% released within 2 hours, 90% by the 4th hour, and prolonged release beyond 8 hours. This profile reduces side effects while increasing efficacy in target cells. Bentonite demonstrated significant drug-loading capacity, controlled release, and tumor-targeting capabilities. At concentrations of 10, 25, 50, and 100 μg/mL, BNT showed dose-dependent antiproliferative effects, maintaining low cytotoxicity at lower concentrations. The combination of azacytidine and bentonite exhibited a synergistic effect in inhibiting cell proliferation, with significant decreases in cell viability in the 1 μM azacytidine + 10 μg/mL bentonite, 5 μM azacytidine + 10 μg/mL bentonite, and 10 μM azacytidine + 10 μg/mL bentonite groups compared to the controls. The combination of 1 μM AZA with 10 μg/mL BNT achieved similar efficacy to 10 μM AZA alone, suggesting a potential for dose reduction and improved safety. Conclusion: BNT nanoparticles are promising carriers for AZA, enhancing targeted delivery, reducing side effects, and potentially lowering the required dose for leukemia treatment. These findings support further investigation into the clinical application of BNT-AZA in hematologic cancers. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of venetoclax combined with azacytidine on T lymphocyte subsets in elderly patients with acute myeloid leukemia (AML), and to analyze the influencing factors of efficacy. Methods: 238 elderly AML patients were divided into control group (n=120, treated with azacitidine) and study group (n=118, treated with venetoclax combine with azacitidine) according to the different treatment options. The efficacy, changes of T lymphocyte subsets and incidence of adverse reactions were compared in two groups. The influencing factors that affect the poor efficacy were analyzed by multivariate logistic regression. Results: Compared with control group, the total clinical effective rate in study group after treatment was higher, CD3+, CD4+, CD4+/CD8+ were higher, and CD8+ was lower (P<0.05). There was no difference in the total incidence of adverse reactions between two groups (P>0.05). Low platelet count (PLT), high lactate dehydrogenase (LDH), and high Chalson comorbidities index (CCI) score were risk factors for poor efficacy (P<0.05). Conclusion: Vinecra combined with azacytidine can effectively improve the clinical efficacy and immune function of elderly AML patients. In addition, the efficacy of elderly AML patients is also affected by PLT, LDH, and CCI scores. [ABSTRACT FROM AUTHOR]

Simple Summary: Azacytidine and donor lymphocyte infusions were combined effectively in a single-center high-risk patient cohort (n = 29) for post-transplant relapse of acute myeloid leukemia and myelodysplastic syndrome. Bone marrow Wilms tumor gene 1 (WT1) expression was measured at time of transplant and post-transplant relapse. By using the Cox proportional hazards model, cut-off values for WT1 at both time points were obtained. The disease risk index incorporating initial cytogenetics and the disease stage at transplant as well as WT1 expression was significantly associated with overall survival, indicating that WT1 may represent a minimal residual disease marker in this context of cell therapy response evaluation, especially in high-risk patients currently considered to be in complete remission. Cut-off values for bone marrow WT1 expression for the two decisive treatment time points were proposed. Introduction: Post-transplant relapse of acute myeloid leukemia and myelodysplastic syndrome faces restricted effective salvage regimens. We retrospectively analyzed the use of Azacitidine–donor lymphocyte infusion (AZA/DLI) in this setting. Furthermore, data on bone marrow Wilms tumor gene 1 (WT1) expression were collected. Methods: A Cox proportional hazards model, an outcome-oriented approach for the lowest smoothed plot of the martingale residuals, was performed for the cut-point determination of the respective WT1 expression levels. Finally, a Cox proportional hazards model investigated the association of overall survival (OS) with predictors. Results: An overall response of 41.4% with a median duration of 11.9 months for stable disease and 19.5 months for complete response (CR) patients was achieved. The disease risk index (DRI) high-/very high-risk patients had a shorter OS of 4.4 months than intermediate-risk patients, with 14.5 months, p = 0.007. At transplant, WT1-overexpressing patients (>150 copies) had a shorter median OS of 5.3 months than low-WT1-expressing ones, with 13.5 months, p = 0.024. Furthermore, patients with ≤1000 WT1 copies at relapse had a significantly longer OS with 15.3 months than patients overexpressing WT1, with 4.4 months, p = 0.0002. Conclusions: DRI and WT1 expression associate significantly with OS after AZA/DLI. Hence, WT1 may represent an MRD marker, especially in CR patients at high risk. [ABSTRACT FROM AUTHOR]

Summary: Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53mut, azacytidine if TET2/KMT2Dmut, tucidinostat if CREBBP/EP300mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12–0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0–26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34–0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28–1.10; p = 0.088). The most common grade 3–4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

Combined therapy with venetoclax and hypomethylating agents has significantly improved the outcome of unfit patients ineligible for intensive chemotherapy. A recently published exploratory analysis of the VIALE-A trial reported that up to 51% of patients achieving remission survived more than 2 years. These data along with those from reallife settings, lead to questioning how long it is appropriate to continue treatment in long-term survivors. Accordingly, recent retrospective studies suggested the feasibility of suspending therapy in selected patients while maintaining prolonged responses. Also, these studies showed that retreatment may induce a second remission in almost a third of patients. We report the case of a patient who received salvage therapy with venetoclax and azacytidine, that was discontinued few cycles after blasts clearance because of severe hematological toxicity. Despite suspension, he maintained a sustained response lasting almost one year and was successfully retreated with the same combination when a second relapse occurred. [ABSTRACT FROM AUTHOR]

Key message: Extensive leaf transcriptome profiling and differential gene expression analysis of field grown and elicited shoot cultures of L. speciosa suggest that differential synthesis of CRA is mediated primarily by CYP and TS genes, showing functional diversity. Lagerstroemia speciosa L. is a tree species with medicinal and horticultural attributes. The pentacyclic triterpene, Corosolic acid (CRA) obtained from this species is widely used for the management of diabetes mellitus in traditional medicine. The high mercantile value of the compound and limited availability of innate resources entail exploration of alternative sources for CRA production. Metabolic pathway engineering for enhanced bioproduction of plant secondary metabolites is an attractive proposition for which, candidate genes in the pathway need to be identified and characterized. Therefore, in the present investigation, we focused on the identification of cytochrome P450 (CYP450) and oxidosqualene cyclases (OSC) genes and their differential expression during biosynthesis of CRA. The pattern of differential expression of these genes in the shoot cultures of L. speciosa, elicited with different epigenetic modifiers (azacytidine (AzaC), sodium butyrate (NaBu) and anacardic acid (AA)), was studied in comparison with field grown plant. Further, in vitro cultures with varying (low to high) concentrations of CRA were systematically assessed for the expression of CYP-TS and associated genes involved in CRA biosynthesis by transcriptome sequencing. The sequenced samples were de novo assembled into 180,290 transcripts of which, 92,983 transcripts were further annotated by UniProt. The results are collectively given in co-occurrence heat maps to identify the differentially expressed genes. The combined transcript and metabolite profiles along with RT-qPCR analysis resulted in the identification of CYP-TS genes with high sequence variation. Further, instances of concordant/discordant relation between CRA biosynthesis and CYP-TS gene expression were observed, indicating functional diversity in genes. [ABSTRACT FROM AUTHOR]

Simple Summary: The study explores a promising treatment avenue for acute myeloid leukemia (AML), emphasizing the drug combination venetoclax and azacitidine (VEN plus AZA) to improve patient survival and enable stem cell transplantation in those unsuitable for intensive chemotherapy. Comparative analysis with conventional treatment shows comparable survival rates, influenced by genetic factors. In conclusion, for older AML patients unable to endure intensive chemotherapy, the VEN plus AZA regimen emerges as a viable, less taxing option, offering the potential for curative stem cell transplantation. Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely recommended for unfit patients with newly diagnosed acute myeloid leukemia (AML). Patient survival can improve with venetoclax plus azacitidine (VEN plus AZA). However, the long-term outcome of this treatment strategy is still unsatisfactory. The high response and low treatment toxicity rates of patients receiving VEN plus AZA can provide an opportunity for HSCT among unfit patients. Nevertheless, the outcomes and complications of VEN plus AZA, followed by HSCT, remain unclear. Methods: This single-center retrospective study aimed to compare patients with newly diagnosed AML receiving VEN plus AZA as induction therapy (n = 27) to those receiving the conventional I3A7 regimen as induction therapy (n = 34). Result: The 1-year overall survival, relapse, and non-relapse mortality rates in the two groups were similar. The cytogenetic risks and the hematopoietic cell transplantation-specific comorbidity index are the most significant predictive factors of overall survival. Conclusion: In older patients unfit for intensive chemotherapy, a low-intensity regimen with VEN plus AZA is a suitable bridge therapy. Furthermore, allo-HSCT is feasible and can be a curative option. [ABSTRACT FROM AUTHOR]

VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by cytopenias and macrocytic anemia. Dyshematopoiesis is a frequent finding in chronic inflammatory conditions and therefore, cytopenias are not easily classified in VEXAS patients. Here we report a series of 7 patients affected by VEXAS associated cytopenias, treated at our center. The use of NGS, together with morphological assays, integrated with the WHO 2022 criteria, allowed to identify three subsets of VEXAS associated cytopenias: ICUS (idiopathic cytopenia of uncertain significance), CCUS (clonal cytopenia of uncertain significance) at high risk of clonal evolution, and MDS. This approach could help to better understand the nature of VEXAS associated cytopenias and to guide the use of specific targeted treatments in order to achieve long lasting responses. [ABSTRACT FROM AUTHOR]

Recurrence following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the major cause of treatment failure in patients with myeloid malignancy. Azacytidine (AZA) maintenance is a promising therapy to prevent relapse and improve survival. We conducted a prospective, one‐arm study involving 78 patients with myeloid malignancy at a high risk of recurrence who were enrolled between September 2019 and April 2022. Furthermore, 102 matched historical controls were selected using propensity score matching. With a median follow‐up time of 19.6 (3.5–91.7) months, AZA maintenance therapy significantly improved relapse‐free survival (RFS; log‐rank test, p = 0.01). The AZA and control groups had a 1‐year RFS of 87.7% (95% confidence interval [CI], 0.80–0.96) and 72.2% (95% CI, 0.64–0.82), respectively, with a hazard ratio (HR) of 0.21 (95% CI, 0.09–0. 47; p < 0.01). There were no grade 4 adverse effects or deaths related to AZA. Refractory patients with favorable/intermediate‐risk acute myeloid leukemia (AML) benefited more from AZA maintenance therapy than those with adverse‐risk AML according to the European Leukemia Net guidelines (RFS in favorable/intermediate‐risk AML, HR = 0.29, 95% CI, 0.11–0.79; RFS in adverse‐risk AML, HR = 0.57, 95% CI, 0.21–1.6; p for interaction = 0.03). Our findings suggest that AZA maintenance therapy following allo‐HSCT was safe and could reduce the incidence of relapse, particularly for refractory patients with favorable/intermediate‐risk AML. [ABSTRACT FROM AUTHOR]

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare leukemia subtype that possibly originates from precursor NK cells. The disease has a poor prognosis, and information on its treatment is lacking. We herein report the first case of a 46-year-old woman with MNKPL who was refractory to two lines of acute myeloid leukemia (AML)-type intensive chemotherapy but was successfully treated with venetoclax and azacytidine (VEN/AZA). She was diagnosed with MNKPL based on the conformations of immature lymphoblastoid morphology without myeloperoxidase reactivity that showed a CD7/CD33/CD34/CD56/HLA-DR positive phenotype and extramedullary regions. The disease was refractory to induction therapy with daunorubicin and cytarabine (DNR/Ara-C) and to reinduction therapy with mitoxantrone, etoposide, and cytarabine (MEC). After two lines of induction chemotherapy, massive pericardial and pleural effusion was found, and was suspected to be extramedullary lesions. The patient developed cardiac tamponade and required pericardiocentesis. Thus, VEN/AZA was administered as third-line therapy. After two cycles of VEN/AZA, the pericardial and pleural effusion disappeared, and complete remission was achieved. The patient received post-transplant cyclophosphamide-based haploidentical transplantation and has stayed relapse-free as of her last follow-up examination 2 years after diagnosis. [ABSTRACT FROM AUTHOR]

Young adults with acute myeloid leukemia (AML) often fail to achieve permanent complete remission (CR) and frequently relapse, indicating an urgent need to explore effective salvage therapies. Recent advances in AML treatment have been attributed to the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax (VEN) with hypomethylating agents (HMAs); however, the use of this combination in young adults with relapsed or refractory (R/R) AML has not been reported. We retrospectively examined 31 young patients with R/R AML treated with VEN plus an HMA. We evaluated the demographic data, cytogenetic characteristics, AML types, response rates, and transplantation-related data for the patients in our cohort. The combination of VEN + HMA yielded a CR rate of 48.4%. The most prominent hematologic adverse event was neutropenia, which occurred in all patients, with 90.3% of cases being grade ≥3. Non-hematologic toxicities were relatively mild and infrequent, with an incidence of 45.2%. More than half of the patients with sustained CR had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT), of whom two died of transplant-related complications. Our results showed that the combination of VEN + HMA appeared to be a highly effective and well-tolerated salvage therapy option for young patients with R/R AML, enabling more young patients to proceed to potentially curative allo-HSCT. However, additional, well-designed studies with larger numbers of patients are required to confirm the advantages of VEN + HMA in this population. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia （AML） is a kind of myeloid clonal proliferative tumor with strong heterogeneity. Chemotherapy and hematopoietic stem cell transplantation are the main treatment methods for AML. Although patients can achieve better therapeutic effects, the elderly people cannot tolerate conventional chemotherapy due to many reasons such as advanced age, physiological and cognitive impairment, and increased complications, with limited treatment options and shorter survival period （only 2 months）. Venetoclax is the first approved B-cell lymphoma/leukemia-2 inhibitor （BCL-2） in the world. Many studies have shown that hypomethylating agents (HMA) such as azacytidine or dexcitabine and other low-intensity chemotherapy regimens combined with venetoclax has good efficacy in elderly patients, significantly improving combined overall response rate and overall survival （CR/Cri 66.4%, median OS 14.7 months）, enable more patients to transition to the allogeneic hematopoietic stem cell transplantation stage （allo-HSCT）. This article briefly reviews the mechanism of action of venetoclax, its clinical application in AML and some related issues including drug resistance.

VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by cytopenias and macrocytic anemia. Dyshematopoiesis is a frequent finding in chronic inflammatory conditions and therefore, cytopenias are not easily classified in VEXAS patients. Here we report a series of 7 patients affected by VEXAS associated cytopenias, treated at our center. The use of NGS, together with morphological assays, integrated with the WHO 2022 criteria, allowed to identify three subsets of VEXAS associated cytopenias: ICUS (idiopathic cytopenia of uncertain significance), CCUS (clonal cytopenia of uncertain significance) at high risk of clonal evolution, and MDS. This approach could help to better understand the nature of VEXAS associated cytopenias and to guide the use of specific targeted treatments in order to achieve long lasting responses.

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis. Dysregulation of the epigenetic machinery is a significant contributor to disease development. Some AML patients benefit from treatment with hypomethylating agents (HMAs), but no predictive biomarkers for therapy response exist. Here, we investigated whether unbiased genome-wide assessment of pre-treatment DNA-methylation profiles in AML bone marrow blasts can help to identify patients who will achieve a remission after an azacytidine-containing induction regimen. Results: A total of n = 155 patients with newly diagnosed AML treated in the AMLSG 12-09 trial were randomly assigned to a screening and a refinement and validation cohort. The cohorts were divided according to azacytidine-containing induction regimens and response status. Methylation status was assessed for 664,227 500-bp-regions using methyl-CpG immunoprecipitation-seq, resulting in 1755 differentially methylated regions (DMRs). Top regions were distilled and included genes such as WNT10A and GATA3. 80% of regions identified as a hit were represented on HumanMethlyation 450k Bead Chips. Quantitative methylation analysis confirmed 90% of these regions (36 of 40 DMRs). A classifier was trained using penalized logistic regression and fivefold cross validation containing 17 CpGs. Validation based on mass spectra generated by MALDI-TOF failed (AUC 0.59). However, discriminative ability was maintained by adding neighboring CpGs. A recomposed classifier with 12 CpGs resulted in an AUC of 0.77. When evaluated in the non-azacytidine containing group, the AUC was 0.76. Conclusions: Our analysis evaluated the value of a whole genome methyl-CpG screening assay for the identification of informative methylation changes. We also compared the informative content and discriminatory power of regions and single CpGs for predicting response to therapy. The relevance of the identified DMRs is supported by their association with key regulatory processes of oncogenic transformation and support the idea of relevant DMRs being enriched at distinct loci rather than evenly distribution across the genome. Predictive response to therapy could be established but lacked specificity for treatment with azacytidine. Our results suggest that a predictive epigenotype carries its methylation information at a complex, genome-wide level, that is confined to regions, rather than to single CpGs. With increasing application of combinatorial regimens, response prediction may become even more complicated. [ABSTRACT FROM AUTHOR]

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America. Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML. Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100–600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7–15.5) and 8 months (95% CI 4.8–11.2). Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials. Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.

Acute myeloid leukemia （AML） is a malignant clonal disease originating from hematopoietic stem/progenitor cells. Chemotherapy is the main treatment. If not effectively treated after 2 courses of standard treatment， these patients can be diagnosed with refractory AML. In this article， a case of refractory AML complicated with disseminated Fusarium infection receiving combined treatment of venetoclax and azacitidine was reported. The patient was diagnosed with AML （M5a） with DNMT3A， IDH2 and BCOR mutations， classified in the moderate group. Standard dose of IA regimen （deoxydaunorubicin + cytarabine） was ineffective， and additional homoharringtonine induction therapy remained ineffective. Subsequently， combined use of venetoclax and azacitidine was adopted and the severity of disease was alleviated. Complete remission was achieved after three cycles of venetoclax combined with azacitidine consolidation therapy. After the first chemotherapy， the patient presented with recurrent fever， purple induration with central necrosis in the upper and lower limbs， and visible subcutaneous liquid mass. Pathological examination suggested Fusarium infection. After amphotericin B combined with voriconazole as antifungal therapy， disseminated Fusarium infection was effectively controlled. This case prompts that combined use of venetoclax and azacitidine yields high remission rate in the treatment of refractory AML. Disseminated Fusarium infection is a rare fatal complication in AML patients after chemotherapy. Early diagnosis and effective antifungal treatment are effective interventions to improve the survival rate of patients.

Copyright of Iraqi Journal of Veterinary Medicine is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Military Medical Science Letters / Vojenské zdravotnické Listy is the property of University of Defence, Faculty of Military Health Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Strawberry ripening involves a number of irreversible biochemical reactions that cause sensory changes through accumulation of sugars, acids and other compounds responsible for fruit color and flavor. The process, which is strongly dependent on methylation marks in other fruits such as tomatoes and oranges, is highly controlled and coordinated in strawberry. Results Repeated injections of the hypomethylating compound 5-azacytidine (AZA) into green and unripe Fragaria × ananassa receptacles fully arrested the ripening of the fruit. The process, however, was reversible since treated fruit parts reached full maturity within a few days after AZA treatment was stopped. Transcriptomic analyses showed that key genes responsible for the biosynthesis of anthocyanins, phenylpropanoids, and hormones such as abscisic acid (ABA) were affected by the AZA treatment. In fact, AZA downregulated genes associated with ABA biosynthetic genes but upregulated genes associated with its degradation. AZA treatment additionally downregulated a number of essential transcription factors associated with the regulation and control of ripening. Metabolic analyses revealed a marked imbalance in hormone levels, with treated parts accumulating auxins, gibberellins and ABA degradation products, as well as metabolites associated with unripe fruits. Conclusions AZA completely halted strawberry ripening by altering the hormone balance, and the expression of genes involves in hormone biosynthesis and degradation processes. These results contradict those previously obtained in other climacteric and fleshly fruits, where AZA led to premature ripening. In any case, our results suggests that the strawberry ripening process is governed by methylation marks.

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America. Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML. Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100–600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7–15.5) and 8 months (95% CI 4.8–11.2). Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials. Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting. [ABSTRACT FROM AUTHOR]

Copyright of Journal of New Medicine is the property of Sun Yat Sen University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic myelomonocytic leukemia is a clonal hematopoietic stem cell disorder with both myelodysplastic and myeloproliferative features, leading to a variable clinical presentation. Some types of skin involvement, such as leukemia cutis and blastic plasmacytoid dendritic cell neoplasia, are associated with poor prognosis. This case study describes a 71-year-old male with high-risk CMML, developing pink-purple skin nodules, which regressed with azacitidine and hydroxyurea treatment. Despite recurrence, disease control was achieved without transformation to acute leukemia. This case highlights the need for vigilant monitoring and adaptable treatment strategies in managing CMML with skin involvement., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Arslan Davulcu et al.)

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies. [ABSTRACT FROM AUTHOR]

Background: Strawberry ripening involves a number of irreversible biochemical reactions that cause sensory changes through accumulation of sugars, acids and other compounds responsible for fruit color and flavor. The process, which is strongly dependent on methylation marks in other fruits such as tomatoes and oranges, is highly controlled and coordinated in strawberry. Results: Repeated injections of the hypomethylating compound 5-azacytidine (AZA) into green and unripe Fragaria × ananassa receptacles fully arrested the ripening of the fruit. The process, however, was reversible since treated fruit parts reached full maturity within a few days after AZA treatment was stopped. Transcriptomic analyses showed that key genes responsible for the biosynthesis of anthocyanins, phenylpropanoids, and hormones such as abscisic acid (ABA) were affected by the AZA treatment. In fact, AZA downregulated genes associated with ABA biosynthetic genes but upregulated genes associated with its degradation. AZA treatment additionally downregulated a number of essential transcription factors associated with the regulation and control of ripening. Metabolic analyses revealed a marked imbalance in hormone levels, with treated parts accumulating auxins, gibberellins and ABA degradation products, as well as metabolites associated with unripe fruits. Conclusions: AZA completely halted strawberry ripening by altering the hormone balance, and the expression of genes involves in hormone biosynthesis and degradation processes. These results contradict those previously obtained in other climacteric and fleshly fruits, where AZA led to premature ripening. In any case, our results suggests that the strawberry ripening process is governed by methylation marks. [ABSTRACT FROM AUTHOR]

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological diseases. In addition to defects in hematologic progenitor and stem cells, dysfunctions in the bone marrow microenvironment (BMM) participate in the MDS pathogenesis. Furthermore, the immune response is deregulated by the pro-inflammatory response prevailing in low-risk MDS, while immunosuppression predominates in high-risk MDS. Mesenchymal stromal cells (MSC), part of the BMM, are characterized by plastic adherent growth and multipotentiality. They exhibit immunomodulatory properties and sustain hematopoiesis. There is conflicting evidence regarding their status in MDS. The aim of this study was to characterize MDS-MSC and evaluate the effect of 5-Azacytidine. Methods: The MSC from MDS patients and controls were cultured and characterized according to the International Society of Cell Therapy recommendations. Immunomodulatory properties were assessed by studying the MSD cytokine production, using the cytometric bead array. We evaluated the effect of 5-Azacytidine on the MSC cytokine production. Results: We included 35 MDS patients and 22 controls. The MSC from patients and controls were cultured and characterized. The MSC from patients showed morphological differences, but there were no differences in immunophenotype or multipotentiality. The interleukin 6 (IL-6) was the main MSC secreted cytokine. The MDS-MSC produced higher levels of IL-6, IL-17, interferon gamma, or interferon γ (INF-γ), and tumor necrosis factor alpha (TNF-α). The in vitro 5-Azacytidine treatment induced a significant decrease in the IL-6 production by MDS-MSC. Conclusions: The MDS-MSC show an increased production of pro-inflammatory cytokines. The in vitro treatment with 5-Azacytidine lead to a significant reduction in the IL-6 production by the MDS-MSC, restoring the IL-6 levels to those found in controls. The MSC produced inflammatory cytokines involved in the MDS pathogenesis, representing a potential future therapeutic target. Moreover, 5-Azacytidine may have a stromal effect, modulating the immune response in MDS.

Abstract Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2′deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

Summary: 5‐Azacitidine has been used before stem cell transplantation in juvenile myelomonocytic leukaemia (JMML) patients. Recently, we have described immunophenotypic features in JMML at diagnosis. Here, our aim was to examine the changes in the immunophenotypic features during azacitidine treatment, correlating it with clinical response. Patients treated with 5‐azacitidine were evaluated at diagnosis and after three and six cycles of medication. Among 32 patients entering the study, 28 patients were examined after three cycles and 25 patients after six. Patients showed a reduction in CD34/CD117+ cells: median 3.35% at diagnosis, 2.8% after three cycles and 1.63% after six. B‐cell progenitors were decreased at diagnosis and decreased after treatment. Monocytes decreased: 11.91% to 6.4% and 4.18% respectively. Complete response was associated with increase in classical monocytes. T lymphocytes, reduced at diagnosis, increased in patients responding to 5‐azacitidine. Immunophenotypic aberrancies including expression of CD7 in myeloid progenitors remained after treatment. This feature was associated with a worse response to treatment, as well as presence of NF1. Immunophenotyping was feasible in all patients. Clinical response was associated with a decrease of myeloid progenitors and monocytes and a rise in T lymphocytes although phenotypic aberrancies persisted. The largest effect was observed after three cycles. [ABSTRACT FROM AUTHOR]

Background/Aim: Prediction of response to azacitidine (AZA) treatment is an important challenge in hematooncology. In addition to protein coding genes (PCGs), AZA efficiency is influenced by various noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and transposable elements (TEs). Materials and Methods: RNA sequencing was performed in patients with myelodysplastic syndromes or acute myeloid leukemia before AZA treatment to assess contribution of ncRNAs to AZA mechanisms and propose novel disease prediction biomarkers. Results: Our analyses showed that lncRNAs had the strongest predictive potential. The combined set of the best predictors included 14 lncRNAs, and only four PCGs, one circRNA, and no TEs. Epigenetic regulation and recombinational repair were suggested as crucial for AZA response, and network modeling defined three deregulated lncRNAs (CTC-482H14.5, RP11-419K12.2, and RP11-736I24.4) associated with these processes. Conclusion: The expression of various ncRNAs can influence the effect of AZA and new ncRNA-based predictive biomarkers can be defined. [ABSTRACT FROM AUTHOR]

Introduction: Hypomethylating agents have become a standard therapy for certain myeloid malignancies.

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

CD47 is a widely expressed cell-surface protein that regulates phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, signal regulatory protein (SIRP)-α, which in turn inhibits phagocytosis. Several targeted CD47 therapeutic antibodies have been investigated clinically; however, how to improve its therapeutic efficacy remains unclear. Herein, we developed a CD47 blocking antibody, named IBI188, that could specifically block the CD47-SIRP-α axis, which transduces the "don't eat me" signal to macrophages. In vitro phagocytosis assays demonstrated the pro-phagocytosis ability of IBI188. Furthermore, several in vivo models were chosen to evaluate the anti-tumor efficacy of IBI188. IBI188 treatment upregulated cell movement- and inflammation-related genes in macrophages. Synergism was observed when combined with an anti-CD20 therapeutic antibody, whose function depends on antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). CD47 expression was evaluated following azacytidine (AZA) treatment, a standard-of-care for patients with multiple myeloma; enhanced anti-tumor efficacy was observed in the combination group in AML xenograft models. Notably, IBI188 treatment increased vascular endothelial growth factor-A (VEGF-A) levels in a solid tumor model, and combined treatment with an anti-VEGF-A antibody and IBI188 resulted in an enhanced anti-tumor effect. These data indicate that IBI188 is a therapeutic anti-CD47 antibody with anti-tumor potency, which can be enhanced when used in combination with standard-of-care drugs for cancer treatment. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71–610) days and 284.5 (95% CI: 81–610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) can become dysfunctional in patients with hematological disorders. An unanswered question is whether age-linked disruption of the bone marrow (BM) microenvironment is secondary to hematological dysfunction or vice versa. We therefore studied MSC function in patients with different hematological disorders and found decreased MHC-II except from one sample with acute myeloid leukemia (AML). The patients' MSCs were able to exert veto properties except for AML MSCs. While the expression of MHC-II appeared to be irrelevant to the immune licensing of MSCs, AML MSCs lost their ability to differentiate upon contact and rather, continued to proliferate, forming foci-like structures. We performed a retrospective study that indicated a significant increase in MSCs, based on phenotype, for patients with BM fibrosis. This suggests a role for MSCs in patients transitioning to leukemia. NFĸB was important to MSC function and was shown to be a potential target to sensitize leukemic CD34+/CD38− cells to azacitidine. This correlated with their lack of allogeneic stimulation. This study identified NFĸB as a potential target for combination therapy to treat leukemia stem cells and showed that understanding MSC biology and immune response could be key in determining how the aging BM might support leukemia. More importantly, we show how MSCs might be involved in transitioning the high risk patient with hematological disorder to AML. [ABSTRACT FROM AUTHOR]

Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor is a novel anti-cancer drug regulating epigenetic mechanisms. Similar to conventional anti-cancer drugs, drug resistance to DAC also has been reported, resulting in tumor recurrence. Our previous study using colorectal cancer HCT116 cells found the decrease in deoxycytidine kinase (dCK) (activation enzyme of DAC) and the increase in cytidine deaminase (inactivation enzyme of DAC) in acquired DAC-resistant HCT116 (HCT116/DAC) cells. The aim of our study was to clarify the involvement of dCK and CDA in DAC resistance. In order to tackle DAC resistance, it was also examined whether other DNMT inhibitors such as azacytidine (AC) and polyphenols are effective in DAC-resistant cancer cells. When dCK siRNA was transfected into HCT116 cells, IC 50 value of DAC increased by about 74-fold and reached that of HCT116/DAC cells with attenuated dCK. dCK siRNA to HCT116 cells also abolished DNA demethylation effects of DAC. In contrast, CDA siRNA to HCT116 cells did not influence the efficacy of DAC. In addition, CDA siRNA to HCT116/DAC cells with increased CDA did not restore the compromised effects of DAC. These results suggested that attenuated dCK but not increased CDA mainly contributed to DAC resistance. Regarding dCK in HCT116/DAC cells, a point mutation with amino acid substitution was observed while the product size and expression of mRNA coding region did not change, suggesting that dCK protein was decreased by post-transcriptional regulation. AC and polyphenols showed no cross-resistance in HCT116/DAC cells. AC but not polyphenols exerted DNA demethylation effect. Among polyphenols, curcumin (Cur) showed the most synergistic cytotoxicity in combination with AC while DNA demethylation effect of AC was partly maintained. Taken together, combination of AC and Cur would be a promising alternative to tackle DAC resistance mainly due to attenuated dCK. [Display omitted] • Attenuated deoxycytidine kinase mainly contributed to acquired decitabine resistance. • Azacytidine exerted DNA demethylation effect in decitabine-resistant cells. • Azacytidine and curcumin enhanced cytotoxicity in decitabine-resistant cells. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are clonal haematopoetic stem cells disorders, characterized by bone marrow dysplasia, ineffecitive haematopoesis and cytopenias. Due to neutropenia, infections are common. A case is presented of a patient with high-risk myelodysplastic syndrome (MDS) complicated by hidradenitis suppurativa that developed in both axillae. Abscesses required multiple incisions and drainage. After five cycles of treatment with azacitidine, the patient underwent allogenic bone marrow transplantation. Unfortunately, six months after the procedure, the patient lost post-transplant chimerism.Treatment with azacitidine was re-started. After the subsequent ten months, blast transformation was observed. Skin lesions in the course of hidradenitis suppurative persisted and were still considerably active. [ABSTRACT FROM AUTHOR]

DNA methylation is an epigenetic process that involves the chemical modification of DNA, leading to the regulation of its transcriptional activity. It is primarily known for the addition of methyl groups to cytosine in DNA. The whitefly Bemisia tabaci is a polyphagous pest insect and a vector that is responsible for transmitting numerous plant viruses, resulting in significant economic losses in agricultural crops globally. In our study, we characterized the expression of two key DNA methylation genes, the DNA methyltransferases Dnmt1 and Dnmt3 , in B. tabaci. Additionally, we explored the impact of inhibiting DNMTs on the miRNA pathway and fitness of whitefly. To investigate the role of the DNA methylation pathway in B. tabaci , we found that the expression of Dnmt1 and Dnmt3 varied across different tissues and developmental stages of B. tabaci. We employed azacytidine (5-AZA) treatment of adults to inhibit DNMTs (DNMT1 and DNMT3). Administration of 5-AZA affected the survival and reproduction of this pest. Moreover, inhibition of DNMTs led to a decrease in the expression of the miRNA pathway core genes Dicer1 and Argonaute1 , which subsequently resulted in reduced expression of Let-7 and miR-184 which are essential microRNAs in the physiology and biology of insects. The study suggests that DNA methyltransferases could be targeted for developing an inhibition strategy to control this pest and vector insect. [Display omitted] • DNA methylation is vitally important to development and reproduction. • The DNA methylation pathway genes are expressed in the ovaries, eggs and the gut. • Administration of 5-Aza caused early death and decreased fecundity in B. tabaci. • It also inhibited the miRNA pathway and downstream miRNAs. • Results revealed the role of DNMTs in reproduction, development of B. tabaci. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma is a rare disease entity of extramedullary myeloid neoplasm that can occur both as an initial isolated myeloid sarcoma without leukemic cell invasion in the peripheral blood and bone marrow, and as the secondary lesion of acute and chronic myeloid leukemias, myelodysplastic syndrome and chronic myeloproliferative neoplasms. Due to its rarity and its frequent emergence as the recurrent lesion after intensive systemic therapy, including allogeneic hematopoietic stem cell transplantation, the standard treatment has not been established for myeloid sarcoma. In this report, we presented an 84-year-old female patient with isolated myeloid sarcoma which progressed to myelodysplastic syndrome and systemic myeloid sarcoma despite various types of conventional anti-leukemic chemotherapies. However, the patient got a durable partial response by the monotherapy of azacitidine, a hypomethylating agent. She received thirteen courses of azacitidine therapy without progression. We discuss the possibility that hypomethylating agents are the novel effective and feasible therapeutic options for myeloid sarcoma, even in cases refractory to or relapsed after intensive systemic treatment. We also discuss the possible future development of hypomethylating agent-containing combinatory therapeutic strategy for myeloid sarcoma, given its direct anti-leukemic effect and immunomodulatory effect. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is one of the ten most common cancers for men and women with an approximate 75% overall 5-year survival. Sixteen histological tumor subtypes exist and the most common are papillary, chromophobe and clear cell renal cell carcinoma (ccRCC) representing 85% of all RCC. Although epigenetically silenced, endogenous retroviral (ERV) genes become activated in tumors and function to ignite immune responses. Research has intensified to understand ERV protein function and their role as tumor antigens and targets for cancer (immune) therapy. ERV-K env is overexpressed and implicated as a therapeutic target for breast cancer, however studies in RCC are limited. In this investigation a human RCC tissue microarray (TMA) (n=374) predominantly consisting of the most common histological tumor subtypes was hybridized with an ERV-K env antibody and correlated with patient clinical data. TMA results showed the highest amount of ERV-K env protein expression and the strongest significant membrane expression in ccRCC versus other RCC subtypes. High ERV-K env total protein expression of all tumor subtypes significantly correlated with low tumor grading and a longer disease specific survival using multivariable analyses. Cell proliferation and invasion were assayed using the kidney cell lines HEK293 with wild-type p53 and a ccRCC cell line MZ1257RC mutated for p53. Transfecting these cell lines with a codon optimized ERV-K113 env overexpressing CMV vector was performed with or without 5'-Aza-2'-deoxycytidine (Aza) treatment to sustain promoter de-methylation. MZ1257RC showed induction of ERV-K113 expression and significantly increased both proliferation and invasion in the presence or absence of Aza. HEK293 cells demonstrated a restriction of ERV-K113 env expression and invasion with no changes in proliferation in the absence of Aza. However, in the presence of Aza despite increased ERV-K113 env expression, an inhibition of HEK293 proliferation and a further restriction of invasion was found. This study supports ERV-K env as a single prognostic indicator for better survival of RCC, which we propose represents a new tumor antigen. In addition, ERV-K env significantly regulates proliferation and invasion depending on p53 status and Aza treatment. [ABSTRACT FROM AUTHOR]

Nous rapportons une observation originale de maladie de Destombes-Rosai-Dorfman multifocale et réfractaire, associée à un syndrome myélodysplasique. Le traitement de la myélodysplasie a permis une très bonne réponse prolongée des 2 pathologies. Un patient de 35 ans était exploré pour une exophtalmie bilatérale, rapportée histologiquement à une maladie de maladie de Destombes-Rosai-Dorfman. Le bilan d'extension retrouvait une atteinte sinusienne, rénale et ganglionnaire. Il était traité successivement, sans succès, par corticoïdes, colchicine, méthotrexate, infliximab, cladribine et tociluzimab. L'apparition secondaire d'une myélodysplasie (AREB score IPSS intermédiaire-2) faisait proposer un traitement d'induction par aracytine et idarubicine, avec entretien par azacytidine pendant 2 ans. Avec un recul de 5 ans, le patient est en rémission du syndrome myélodysplasique et de la maladie de Destombes-Rosai-Dorfman. Notre observation discute l'intérêt du traitement du syndrome myélodysplasique, dans la prise en charge des manifestations extra-hématologiques associées. We report an original observation of multifocal refractory Destombes-Rosai-Dorfman disease associated with a myelodysplastic syndrome. The treatment of myelodysplasia allowed a good and prolonged response of both pathologies. A 35-year-old patient was investigated for bilateral exophthalmia, histologically related to Destombes-Rosai-Dorfman disease. The extension workup showed sinus, kidney and lymph node involvement. It was treated unsuccessfully with corticosteroids, colchicine, methotrexate, infliximab, cladribine and tociluzimab. The secondary appearance of myelodysplasia (AREB IPSS score intermediate-2) led to induction treatment with aracytin and idarubicin, and maintenance with azacytidine for 2 years. With 5 years of follow-up, the patient is in remission both of the myelodysplastic syndrome and Destombes-Rosai-Dorfman disease. Our observation discusses the interest of the treatment of myelodysplastic syndrome for the management of associated extra-hematological manifestations. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCLs) are an aggressive form of non-Hodgkin lymphomas. PTCLs have multiple subtypes, with PTCL not otherwise specified (PTCL-NOS) being the most common. This subtype usually has a high rate of relapse. Making an accurate diagnosis requires molecular genetic analyses, histopathological examination, and immunophenotyping. Treatment for PTCL traditionally starts with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). We present a case of a patient with PTCL-NOS who progressed despite multiple treatment regimens, including both traditional and novel therapeutic agents, and finally achieved good results with azacytidine, selected based on a TET2 mutation. This case proposes future research into Azacytidine's efficacy in this patient population and further exploration of the broader utility of epigenetic therapies in PTCL., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Le et al.)

To determine the impact of peripheral blood (PB) Wilms’ tumour 1 (WT-1) mRNA levels in patients with primary myelodysplastic syndromes (MDS), we analysed the relationships between several clinical variables at the time of diagnosis and the haematological response of patients treated with azacytidine. We observed overall responses in 20 (63%) patients; there were no significant differences in clinical variables, including bone marrow blast counts, IPSS scores and IPSS-R risk scores, between responders and non-responders. The responders’ PB WT-1 mRNA levels were significantly lower than those of non-responders (P = 0.03). PB WT-1 mRNA expression could be a marker for predicting the response to azacytidine in patients with de novo MDS.

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment.Aim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study.Methods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1–7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response.Results: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2–16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay.Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.

Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2'deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect. [ABSTRACT FROM AUTHOR]

Hypomethylating agents (HMAs) are widely used in patients with higher‐risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine‐2,3‐dioxygenase (IDO‐1) has not yet been evaluated. We observed moderate to strong IDO‐1 expression in 37% of patients with high‐risk MDS. IDO‐1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO‐1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO‐1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO‐1+ MDS, suggesting that IDO‐1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO‐1 is expressed in more than one‐third of patients with higher‐risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO‐1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal. [ABSTRACT FROM AUTHOR]