Biological effect of azacitidine (CC-486) on diffuse large B-cell lymphoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA660788 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12566500.fastq.gz | Fastqsanger.gz | |||
| SRR12566501_1.fastq.gz | Fastqsanger.gz | |||
| SRR12566501_2.fastq.gz | Fastqsanger.gz | |||
| SRR12566502.fastq.gz | Fastqsanger.gz | |||
| SRR12566503.fastq.gz | Fastqsanger.gz |
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Project description:Biomarker study for a phase 1, Open-Label, multicenter trial of azacitidine (CC-486) plus R-CHOP in subjects with high-risk previously untreated diffuse large B-cell lymphoma
2022-06-29 | GSE157302 | GEO
Project description:TCL with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486), a DNA methyltransferase inhibitor, plus CHOP as initial treatment for PTCL and prioritized enrollment for PTCL-TFH (ClinicalTrials.gov - NCT03542266). CC-486 at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was end-of-treatment CR. Secondary endpoints included ORR, safety and survival. Correlative studies assessed mutations, gene expression and methylation in tumor samples. Grade 3-4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Non-hematologic toxicities included fatigue (14%) and GI symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n=17). At a median follow-up of 21 months, 2-yr PFS was 65.8% for all and 69.2% for PTCL-TFH, while 2-yr OS was 68% for all and 75.6% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with TET2 mutations significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), and DNMT3A mutations associated with adverse PFS (p=0.016). CC-486 priming upregulated genes related to apoptosis (p<0.01) and inflammation (p<0.01), with a decrease in TFH proliferation based on gene expression and cell-type deconvolution analysis. DNA methylation did not show significant shift. This safe and active initial therapy regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL.
2023-06-12 | GSE214980 | GEO
Project description:Biological effect of azacitidine (CC-486) on peripheral T-cell lymphoma
| PRJNA887824 | ENA
Project description:This is a phase 2 study of investigational drug, durvalumab given in combination with azacitidine (CC-486). The main purpose of this phase 2 study is to assess the antitumor activity of azacitidine in combination with durvalumab patients with microsatellite stable colorectal carcinoma (MSS-CRC), platinum resistant epithelial ovarian cancer type II (PR-OC), and estrogen receptor positive and HER2 negative breast cancer.
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Project description:Purpose: To evaluate whether administration of the oral DNA hypomethylating agent (HMA) CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.
2020-07-26 | GSE147537 | GEO
Project description:CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.
| S-EPMC6221082 | biostudies-literature
Project description:The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with >30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.
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Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous disease with poor prognosis associated with high-risk molecular features. We report the discovery of golcadomide (CC-99282), a novel cereblon-modulating agent, that induces faster and deeper degradation of hematopoietic transcription factors Ikaros/Aiolos compared with first-generation degraders such as lenalidomide. In vitro, golcadomide induced interferon-stimulated genes, promoted apoptosis, robust antiproliferation, and immunogenic cell death, independent of clinical outcome determinators observed with standard care treatment. In vivo, golcadomide exhibited enhanced antitumor activity, resulting in significant tumor regression and tumor-free animals in lymphoma xenograft models. Pharmacological and CRISPR-based screenings demonstrated that targeting apoptosis, cell cycle progression, NF-kB signaling, and nuclear cytoplasmic transport increased antitumor efficacy of golcadomide. In summary, these data represent the discovery of golcadomide as a promising drug candidate for DLBCL and highlight the rationales for future golcadomide-based combination regimens that could improve clinical outcomes for patients.
2025-10-10 | GSE262641 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common aggressive non-Hodgkin lymphoma, demonstrates significant molecular heterogeneity and suboptimal clinical outcomes. Notably, 10%-15% of patients develop primary refractory disease following first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. While epigenetic modulators have emerged as potential therapeutic options for these high-risk cases, clinical application of broad-spectrum DNA methyltransferase inhibitors such as decitabine and azacitidine remains limited by their multi-target toxicity profiles. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1) plays a critical oncogenic role in DLBCL pathogenesis.
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common aggressive non-Hodgkin lymphoma, demonstrates significant molecular heterogeneity and suboptimal clinical outcomes. Notably, 10%-15% of patients develop primary refractory disease following first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. While epigenetic modulators have emerged as potential therapeutic options for these high-risk cases, clinical application of broad-spectrum DNA methyltransferase inhibitors such as decitabine and azacitidine remains limited by their multi-target toxicity profiles. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1) plays a critical oncogenic role in DLBCL pathogenesis.
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