Background Acute myeloid leukemia (AML) is one of the most common hematologic malignancies with a poor prognosis and high recurrence rate. The discovery of new predictive models and therapeutic agents plays a crucial role. Methods The differentially expressed gene that was explicitly highly expressed in The Cancer Genome Atlas (TCGA) and GSE9476 transcriptome databases were screened and included in the least absolute shrinkage and selection operator (LASSO) regression model to derive risk coefficients and build a risk score model. Functional enrichment analysis was conducted on the screened hub genes to explore the potential mechanisms. Subsequently, critical genes were incorporated into a nomogram model based on risk scores to analyze prognostic value. Finally, this study combined network pharmacology to find potential natural compounds for hub genes and used molecular docking to verify the binding ability of molecular structures to natural compounds to explore drug development for possible efficacy in AML. Results A total of 33 highly expressed genes may be associated with poor prognosis of AML patients. After LASSO and multivariate Cox regression analysis of 33 critical genes, Rho-related BTB domain containing 2 ( RHOBTB2 ), phospholipase A2 ( PLA2G4A ), interleukin-2 receptor-α ( IL2RA ), cysteine and glycine-rich protein 1 ( CSRP1 ), and olfactomedin-like 2A ( OLFML2A ) were found to played a significant role in the prognosis of AML patients. CSRP1 and OLFML2A were independent prognostic factors of AML. The predictive power of these 5 hub genes in combination with clinical features was better than clinical data alone in predicting AML in the column line graphs and had better predictive value at 1, 3, and 5 years. Finally, through network pharmacology and molecular docking, this study found that diosgenin in Guadi docked well with PLA2G4A , beta-sitosterol in Fangji docked well with IL2RA , and OLFML2A docked well with 3,4-di-O-caffeoylquinic acid in Beiliujinu. Conclusions The predictive model of RHOBTB2 , PLA2G4A , IL2RA , CSRP1 , and OLFML2A combined with clinical features can better guide the prognosis of AML. In addition, the stable docking of PLA2G4A , IL2RA , and OLFML2A with natural compounds may provide new options for treating AML.
7513 Background: Follicular lymphoma (FL) is generally considered incurable with patients (pts) often experiencing multiple relapses requiring varying lines of subsequent treatments. Abexinostat (Abx) is a novel potent oral pan- Histone Deacetylase Inhibitor (HDACi) with a pharmacokinetic profile that allows maintenance of sufficient drug concentrations for anti-tumor activity with twice daily (BID) dosing. In prior phase 1/2 studies, Abx was shown to be well-tolerated with significant clinical activity and durable responses in patients with Relapsed/Refractory (R/R) FL. Methods: This open label, single arm study is being conducted to assess the efficacy and safety of Abx in pts with R/R FL. Adults with histologically confirmed grade 1, 2 or 3a FL who have previously received at least 2 lines of therapies, and ECOG PS of 0-2 are being recruited. Abx is administered orally at 80 mg BID 4 hours apart in “one week on, one week off” schedule (Days 1 to 7 & 15 to 21 of a 28-day cycle). Pts undergo efficacy assessment by enhanced CT/MRI every 8 weeks for the first 24 weeks, and every 12 weeks thereafter, and PET-CT at weeks 12 and 24 and to confirm a complete response, in accordance with the Lugano 2014 criteria. The primary endpoint is overall response rate (ORR) assessed by independent review committe (IRC), defined as the % of pts who achieve complete response (CR) or partial response (PR). Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In a planned interim futility analysis conducted with the first 37 pts, if <12/37 (32%) responded (CR or PR), the study was to be terminated. Results: Between June 17, 2020 and Jan 28, 2022, 41 pts received Abx. 37 pts underwent at least one post baseline tumor assessment. Median age was 55 (range 34 – 79), 46% of pts were male, 70% had stage IV disease and 24% had >3 FLIPI-2. Pts had a median of 3 prior lines of therapy (range 2-6), and 22% were refractory to the last prior treatment. As of the data cutoff date on Jan 31, 2022, of 37 pts evaluable for efficacy, the ORR was 70% (26/37 pts), 16% CR (6/37) and the disease control rate was 92% (34/37). The median time to response was 10.8 weeks. The study has met the pre-defined stage I criteria and has entered stage II, aiming to enroll up to 81 evaluable pts. Of 41 pts evaluable for safety, the most common treatment emergent adverse events (TEAEs) (≥ 30%) were thrombocytopenia (85%), diarrhea (61%), neutropenia (54%), leukopenia (49%), asthenia (39%), nausea (37%), and anemia (34%). Grade ≥ 3 TEAEs (≥ 5%) included thrombocytopenia (41%), neutropenia (27%), leukopenia (7%), lymphopenia (7%), prolonged QT (7%), and anemia (5%). One pt discontinued treatment due to AEs. Conclusions: Oral Abx demonstrated promising efficacy and was well tolerated in patients with R/R FL. Clinical trial information: NCT03934567.
Introduction Current treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma‐derived FVIII is short in China. Purpose To evaluate the efficacy and safety of a new B‐domain deleted (BDD) recombinant FVIII (TQG202) produced by human‐derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha. Methods This multicentre, clinical trial consisted of an open‐label, randomized, two‐period cross‐over trial assessing single‐dose pharmacokinetics (PK), and a single‐arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single‐dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded. Results Twenty‐six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2–2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026–.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors. Conclusion TQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.
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