Azacytidine and venetoclax combination regimen (AZA/VEN) is the standard of care in AML settings for unfit to intensive chemotherapy patients. However, AZA/VEN is associated with an increased ...hematological toxicity compared to AZA alone. In this context, alternative AZA/VEN regimens emerged progressively based on each physician experience and local procedures. Moreover, AZA/VEN is now recognized as a valuable therapeutic option in R/R settings, even if no prospective trials addressed this question. In this multicenter study, we aimed to evaluate the efficacy and safety of various AZA/VEN regimen in frontline and R/R patients diagnosed with AML. We retrospectively analyzed 108 patients from 6 different French centers in Auvergne Rhône Alpes (AURA) region, between January 2019 and December 2022. The entire cohort was composed of 64 and 44 patients in frontline and R/R settings. Regarding European LeukemiaNet 2017 risk groups, 12%, 31.5% and 53.7% were favorable, intermediate and unfavorable, respectively. In frontline settings, composite complete remission (CRc) rate was 55.5% and median overall survival (OS) was 11.9 months. Venetoclax dosage (400 mg vs 100 mg/d) and duration per cycle (28 days vs others) did not seem to influence significantly CRc rate probability. Febrile neutropenia (FN) occurred in 59.3%, 23.3% and 18.3% in Cycles 1, 2 and 3, respectively. In or outpatient management for Cycle 1 did not influence FN incidence. During Cycle 1, shorter venetoclax duration regimens (<21 days/cycle) was associated with lower FN (40% vs 66%, P=0.03) compared to ≥21-day VEN cycle. Regarding impact of azole on invasive fungal infection frequency, there was no difference between azole-exposed and non-exposed patients. In R/R settings, CRc rate was 43.8% and OS was 7.9 months. As in frontline settings, VEN dosage and duration per cycle did not influence CR rate probability. In this real-life-settings study, our results suggested that alternative AZA/VEN regimens were not associated with lower response rate and OS. Reducing VEN exposure during Cycle 1 may reduce FN incidence without significant consequences on CR rate probability. An update with 110 additional patients will be presented at the meeting.
Summary
The regimen of 5‐azacytidine for patients with myelodysplastic syndrome (MDS) has remained unchanged since its first approval. Although several modifications have since been made and delays ...and dose reductions are common especially during the first treatment cycles, there are minimal data on the prognostic effect of these modifications. In this study, based on data from 897 patients with MDS treated with 5‐azacytidine recorded in a national registry, the effect of treatment delays and dose reductions on response, transformation to acute myeloid leukaemia, and survival (after 5‐azacytidine initiation, OST) were analysed. Delays during the first two cycles were noted in 150 patients (16·7%) and were found to adversely affect OST independently of the International Prognostic Scoring System score hazard ratio (HR), 1·368; P = 0·033 or pre‐existing neutropenia (HR, 1·42; P = 0·015). In patients achieving a response, delays before response achievement were correlated with its type (complete remission, 2·8 days/cycle; partial remission, 3·3 days/cycle; haematologic improvement, 5·6 days/cycle; P = 0·041), while delays after response achievement did not have any effect on retention of response or survival. Dose reductions were found to have no prognostic impact. Based on our results, treatment delays especially during the first cycles should be avoided, even in neutropenic patients. This strict strategy may be loosened after achieving a favourable response.
Hypomethylating agents have become a standard therapy for certain myeloid malignancies.
The aim of this preliminary study was to assess efficacy and safety of azacitidine in patients with ...myelodysplas tic syndromes (MDS), chronic myelomonocytic leukemia with 10-29% blasts (CMML-2) and acute myeloid leukemia (AML) treated in a single center.
Twenty-six (69% male and 31% female, median age 67.8 years) patients (MDS, = 15; CMML-2, n = 2; AML, n = 9) treated with azacytidine in the period April 2017 to October 2018 year were included in the study. Disease assessment was performed after the 3rd cycle, 6th cycle, and at progression.
The median number of administered cycles was 6 (1-16). Erythroid response was achieved in 46.7% after 3rd cycle and 66.7% after 6th cycle. Platelet response was reached in 72.7% after 3rd cycle and 40% after 6th cycle and neutrophil hematological improvement in 27.3% and 50%, respectively. Only one patient (8.3%) progressed after the 6th cycle, stable disease or better marrow response was achieved in the others. The median progression free survival (PFS) and overall survival (OS) were 7.9 and 10.7 months in the MDS group and 9.7 and 11.5 months in the AML group, respectively. None of the patients with CMML-2 progressed at the end of the study. The only found factor to correlate with shortened PFS and OS was IPSS high risk MDS. The most frequent grade ≥ 3 adverse events was neutropenia 38.5%, followed by anemia 15.4% and thrombocytopenia 11.5%.
The therapy with azacitidine is an option for elderly patients with high-risk MDS, AML and CMML-2 that provides PFS and OS for approximately one year irrespective of age or nosological subgroup. These are preliminary data and larger patient cohort and longer follow-up period are needed for clinical conclusions.
The primary objective is overall response rate (CR/CRi).
This is a single-institution, single-arm, phase II study of pre-treatment with azacytidine followed by FLAG for the treatment of relapsed or ...refractory AML.
Salvage therapy in relapsed/refractory AML.
Patients with relapsed or refractory AML, ECOG performance status ≤2, and patients with preserved organ function. Exclusion criteria: Patients with a diagnosis of acute promyelocytic leukemia (AML-M3), pregnant women, patients previously treated with fludarabine, and patients with uncontrolled intercurrent illness. Twenty-one patients were enrolled, and all were evaluable for toxicity and response. The median number of prior treatments was 1 (range: 1–3). Nine patients (43%) were refractory to the most recent treatment, while most other patients relapsed less than 6 months from the last treatment before enrollment.
Azacytidine was given at 75 mg/m2 per day for 5 days prior to the standard FLAG therapy.
Primary study endpoints were safety and ORR ORR = CR, CRi, PR, morphologic leukemia-free state (MLFS) according to the International Working Group criteria, overall survival, and relapse-free survival.
Bone marrow suppression was the most common adverse event and was observed in all patients. The 30-day mortality was noted in 2 patients (10%), related to infection/septic shock with multi-organ failure. The combination was tolerated, and toxicities were as expected for patients receiving salvage intensive chemotherapy. The CR/CR with incomplete blood count recovery (CRi) rate was 53%. Of the 9 primary refractory patients, 5 (56%) achieved CR/CRi. Eight of 11 patients who achieved CR/CRi also attained minimal residual disease-negative status (≤1.0% by flow cytometry), and 8 patients (73%) went for stem cell transplant. Of the 11 patients who achieved CR/CRi, 5 were still alive on the last follow-up. The overall survival for the entire cohort was 4.1 months, and relapse-free survival was 4.7 months.
AZA FLAG combination is safe and does not seem to have an added benefit in response rate or survival.
Cancer recurrence after surgery remains an unresolved clinical problem
. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required ...for disseminating tumour cells to engraft distant sites
. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment
. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.
Direct reprogramming of cardiac fibroblasts to induced cardiomyocytes (iCMs) is a promising approach to cardiac regeneration. However, the low yield of reprogrammed cells and the underlying ...epigenetic barriers limit its potential. Epigenetic control of gene regulation is a primary factor in maintaining cellular identities. For instance, DNA methylation controls cell differentiation in adults, establishing that epigenetic factors are crucial for sustaining altered gene expression patterns with subsequent rounds of cell division. This study attempts to demonstrate that 5′AZA and miR-133a encapsulated in PLGA-PEI nanocarriers induce direct epigenetic reprogramming of cardiac fibroblasts to cardiomyocyte-like cells. The results present a cardiomyocyte-like phenotype following seven days of the co-delivery of 5′AZA and miR-133a nanoformulation into human cardiac fibroblasts. Further evaluation of the global DNA methylation showed a decreased global 5-methylcytosine (5-medCyd) levels in the 5′AZA and 5′AZA/miR-133a treatment group compared to the untreated group and cells with void nanocarriers. These results suggest that the co-delivery of 5′AZA and miR-133a nanoformulation can induce the direct reprogramming of cardiac fibroblasts to cardiomyocyte-like cells in-vitro, in addition to demonstrating the influence of miR-133a and 5′AZA as epigenetic regulators in dictating cell fate.
Epigenetic reprogramming and autophagy have critical roles in differentiation of stem cells. However, very little is known about how epigenetic modifications are mediated and how they contribute to ...autophagy and differentiation in human cardiac stem cells (hCSCs). Previously, we have reported that intracellular matrix metalloproteinase‐9 (MMP9), a collagenase, mediates cell death in hCSCs. Here, we investigated whether intracellular MMP9 mediates epigenetic modifications and autophagy in hCSCs. We created MMP9KO hCSCs and treated them with 5‐azacytidine, an inhibitor of DNA methylation, and bafilomycin A1, an inhibitor of autophagosome degradation, and evaluated epigenetic modifications, autophagic flux, and differentiation. Our results showed compromised epigenetic modifications, reduced autophagy, and impaired differentiation in MMP9KO hCSCs. Remarkably, paracrine MMP9 supplementation restored epigenetic modifications but further reduced autophagy in MMP9KO hCSCs. We conclude that intracellular MMP9 is a critical mediator of epigenetic modifications and autophagy in hCSCs. Furthermore, the endocrine and paracrine effects of MMP9 vary for regulating autophagy in hCSCs. These novel roles of MMP9 are valuable for stem cell therapy.
Deficiency of matrix metalloproteinase‐9 (MMP9) compromises epigenetic modifications, reduces autophagy, and impairs differentiation of human cardiac stem cells (hCSCs). In hCSCs, treatment with 5‐azacytidine decreases epigenetic modifications and autophagy, which are similar to MMP9KO hCSCs. Paracrine MMP9 supplementation improves epigenetic modification but further decreases autophagy in MMP9KO hCSCs. We used BioRender to prepare this figure.
RNA methylation and cancer treatment Yang, Baochen; Wang, Jing-Quan; Tan, Yao ...
Pharmacological research,
December 2021, 2021-12-00, 20211201, Letnik:
174
Journal Article
Recenzirano
Odprti dostop
To this date, over 100 different types of RNA modification have been identified. Methylation of different RNA species has emerged as a critical regulator of transcript expression. RNA methylation and ...its related downstream signaling pathways are involved in plethora biological processes, including cell differentiation, sex determination and stress response, and others. It is catalyzed by the RNA methyltransferases, is demethylated by the demethylases (FTO and ALKBH5) and read by methylation binding protein (YTHDF1 and IGF2BP1). Increasing evidence indicates that this process closely connected to cancer cell proliferation, cellular stress, metastasis, immune response. And RNA methylation related protein has been becoming a promising targets of cancer therapy. This review outlines the relationship between different types of RNA methylation and cancer, and some FTO inhibitors in cancer treatment.
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