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Blood Advances Jul 2023CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in...
CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in adults with relapsed/refectory multiple myeloma (RRMM) with 1 to 3 prior therapies. The CANDOR study met its primary end point of progression-free survival (PFS) in the primary analysis. Here, we report the final analysis of the study, including secondary end points and subgroup analyses thereof. The median follow-up was 50 months. Patients treated with KdD had higher minimal residual disease-negative (MRD-) achievement rates (28% vs 9%; odds ratio [OR], 4.22; 95% confidence interval [95% CI], 2.28-7.83) and MRD- complete response rates (22% vs 8%; OR, 3.55; 95% CI, 1.83-6.88) than those treated with Kd. Median PFS was 28.4 months for KdD vs 15.2 months for Kd (hazard ratio [HR], 0.64; 95% CI, 0.49-0.83). Median overall survival (OS) for KdD was 50.8 months vs 43.6 months for Kd (HR, 0.78 [0.60-1.03]; P = .042). Trends toward improved OS occurred in predefined subgroups, including patients refractory to lenalidomide (KdD, not reached vs Kd, 38.2 months; HR, 0.69 [0.43-1.11]) and refractory to proteasome inhibitor (KdD, 43.2 months vs Kd, 30.0 months; HR, 0.70 [0.45-1.09]), and there was significant improvement in patients with high-risk cytogenetics (KdD, 34.3 months vs Kd: 17.1 months; HR, 0.52 [0.29-0.94]). No new safety signals were identified. In summary, the final analysis of CANDOR confirmed the PFS benefit and showed a trend in OS benefit with KdD vs Kd. These findings reinforce KdD as a standard of care for RRMM, especially in clinically relevant patient subgroups. This trial was registered at www.clinicaltrials.gov as #NCT03158688.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma
PubMed: 37163358
DOI: 10.1182/bloodadvances.2023010026 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2020In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.
PATIENTS AND METHODS
Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression.
RESULTS
Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed.
CONCLUSION
After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Time Factors
PubMed: 32482541
DOI: 10.1016/j.clml.2019.09.623 -
JAMA Oncology Jul 2022The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial.
IMPORTANCE
The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking.
OBJECTIVE
To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL).
DESIGN, SETTING, AND PARTICIPANTS
This was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group.
INTERVENTIONS
Patients in each group were treated with the assigned regimen every 21 days for 6 cycles.
MAIN OUTCOMES AND MEASURES
The primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared.
RESULTS
Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01501149.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Female; Humans; Killer Cells, Natural; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged
PubMed: 35708709
DOI: 10.1001/jamaoncol.2022.1968 -
Acta Biomaterialia Aug 2022The acute lung injury (ALI) is an inflammatory disorder associated with cytokine storm, which activates various reactive oxygen species (ROS) signaling pathways and...
The acute lung injury (ALI) is an inflammatory disorder associated with cytokine storm, which activates various reactive oxygen species (ROS) signaling pathways and causes severe complications in patients as currently seen in coronavirus disease 2019 (COVID-19). There is an urgent need for medication of the inflammatory lung environment and effective delivery of drugs to lung to reduce the burden of high doses of medications and attenuate inflammatory cells and pathways. Herein, we prepared dexamethasone-loaded ROS-responsive polymer nanoparticles (PFTU@DEX NPs) by a modified emulsion approach, which achieved high loading content of DEX (11.61 %). DEX was released faster from the PFTU@DEX NPs in a ROS environment, which could scavenge excessive ROS efficiently both in vitro and in vivo. The PFTU NPs and PFTU@DEX NPs showed no hemolysis and cytotoxicity. Free DEX, PFTU NPs and PFTU@DEX NPs shifted M1 macrophages to M2 macrophages in RAW264.7 cells, and showed anti-inflammatory modulation to A549 cells in vitro. The PFTU@DEX NPs treatment significantly reduced the increased total protein concentration in BALF of ALI mice. The delivery of PFTU@DEX NPs decreased the proportion of neutrophils significantly, mitigated the cell apoptosis remarkably compared to the other groups, reduced M1 macrophages and increased M2 macrophages in vivo. Moreover, the PFTU@DEX NPs had the strongest ability to suppress the expression of NLRP3, Caspase1, and IL-1β. Therefore, the PFTU@DEX NPs could efficiently suppress inflammatory cells, ROS signaling pathways, and cell apoptosis to ameliorate LPS-induced ALI. STATEMENT OF SIGNIFICANCE: The acute lung injury (ALI) is an inflammatory disorder associated with cytokine storm, which activates various reactive oxygen species (ROS) signaling pathways and causes severe complications in patients. There is an urgent need for medication of the inflammatory lung environment and effective delivery of drugs to modulate the inflammatory disorder and suppress the expression of ROS and inflammatory cytokines. The inhaled PFTU@DEX NPs prepared through a modified nanoemulsification method suppressed the activation of NLRP3, induced the polarization of macrophage phenotype from M1 to M2, and thereby reduced the neutrophil infiltration, inhibited the release of proteins and inflammatory mediators, and thus decreased the acute lung injury in vivo.
Topics: Acute Lung Injury; Animals; Cytokine Release Syndrome; Dexamethasone; Lipopolysaccharides; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Nanoparticles; Pneumonia; Polymers; Reactive Oxygen Species; COVID-19 Drug Treatment
PubMed: 35724918
DOI: 10.1016/j.actbio.2022.06.024 -
Science Advances Jun 2023Dexamethasone (DEX) is the first drug to show life-saving efficacy in patients with severe coronavirus disease 2019 (COVID-19), while DEX is associated with serious...
Dexamethasone (DEX) is the first drug to show life-saving efficacy in patients with severe coronavirus disease 2019 (COVID-19), while DEX is associated with serious adverse effects. Here, we report an inhaled, Self-immunoregulatory, Extracellular Nanovesicle-based Delivery (iSEND) system by engineering neutrophil nanovesicles with cholesterols to deliver DEX for enhanced treatment of COVID-19. Relying on surface chemokine and cytokine receptors, the iSEND showed improved targeting to macrophages and neutralized broad-spectrum cytokines. The nanoDEX, made by encapsulating DEX with the iSEND, efficiently promoted the anti-inflammation effect of DEX in an acute pneumonia mouse model and suppressed DEX-induced bone density reduction in an osteoporosis rat model. Relative to an intravenous administration of DEX at 0.1 milligram per kilogram, a 10-fold lower dose of nanoDEX administered by inhalation produced even better effects against lung inflammation and injury in severe acute respiratory syndrome coronavirus 2-challenged nonhuman primates. Our work presents a safe and robust inhalation delivery platform for COVID-19 and other respiratory diseases.
Topics: Mice; Rats; Animals; COVID-19; Cytokine Release Syndrome; COVID-19 Drug Treatment; Nanoparticles; Dexamethasone; Primates
PubMed: 37315135
DOI: 10.1126/sciadv.adg3277 -
Haematologica Feb 2024Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need,... (Clinical Trial)
Clinical Trial
Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Recurrence
PubMed: 37584290
DOI: 10.3324/haematol.2023.283073 -
Microbiome Nov 2023Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with...
BACKGROUND
Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with neurological diseases; however, the mechanisms by which the microbiota regulates postoperative gastrointestinal and cognitive function are incompletely understood.
METHODS
Behavioral testing, MiSeq 16S rRNA gene sequencing, non-target metabolism, intestinal permeability detection, protein assays, and immunofluorescence staining were employed to discern the impacts of surgery on microbial profiles, intestinal barriers, serum metabolism, and the brain. Interventions in mice included fecal microbiota transplantation, the anti-inflammatory agent dexamethasone, Lactobacillus supplementation, indole propionic acid supplementation, and palmitic amide administration.
RESULTS
Surgery-induced cognitive impairment occurs predominantly in aged mice, and surgery-induced alterations in the microbiota composition profile exacerbate intestinal barrier disruption in aged mice. These adverse effects can be mitigated by transferring microbiota from young donors or by bolstering the intestinal barrier function using dexamethasone, Lactobacillus, or indole propionic acid. Moreover, microbiota composition profiles can be restored by transplanting feces from young mice to aged surgical mice, improving neuropathology and cognitive function, and these effects coincide with increased intestinal permeability. Metabolomic screening identified alterations in metabolites in mouse serum after surgery, especially the increase in palmitic amide. Palmitic amide levels in serum and brain can be decreased by transplanting feces from young mice to aged surgical mice. Oral palmitic amide exacerbates cognitive impairment and neuropathological changes in mice.
CONCLUSIONS
Gut microbial dysbiosis in mice after surgery is a key mechanism leading to cognition dysfunction, which disrupts the intestinal barrier and metabolic abnormalities, resulting in neuroinflammation and dendritic spine loss. Intestinal barrier damage and high level of palmitic amide in old mice may be the cause of high incidence of PND in the elderly. Preoperative microbiota regulation and intestinal barrier restoration may be of therapeutic benefit in preventing PND. Video Abstract.
Topics: Animals; Mice; Cognitive Dysfunction; Dexamethasone; Dysbiosis; Gastrointestinal Microbiome; Indoles; Mice, Inbred C57BL; RNA, Ribosomal, 16S
PubMed: 37936242
DOI: 10.1186/s40168-023-01689-6 -
Journal of Perinatal Medicine Nov 2023Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects. (Review)
Review
BACKGROUND
Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects.
CONTENT
A systematic review was performed to determine the childhood and adolescent cardiopulmonary and cognitive effects of dexamethasone systemically administered to preterm infants during neonatal intensive care. Relevant studies were identified by searching two electronic health databases and the grey literature. Spirometry assessments were used as respiratory outcomes, blood pressure and echocardiography assessments as cardiovascular outcomes and cognitive and motor function as cognitive outcomes. From 1,479 articles initially identified, 18 studies (overall 1,609 patients) were included (respiratory n=8, cardiovascular n=2, cognitive n=10); all were observational cohort studies. Dexamethasone exposure was associated with worse pulmonary outcomes in children and adolescents (more abnormal FVC and FEV1:FVC z scores). Dexamethasone exposure was associated in one study with lower IQ scores compared to preterm controls (mean 78.2 [SD 15.0] vs. 84.4 [12.6], [p=0.008]) and in two others was associated with lower total and performance IQ when compared to term controls (p<0.001).
SUMMARY AND OUTLOOK
Postnatal dexamethasone exposure has a negative influence on pulmonary and cognitive outcomes in childhood and adolescence. Medications with a better benefit to risk profile need to be identified.
Topics: Adolescent; Child; Humans; Infant; Infant, Newborn; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Bronchopulmonary Dysplasia; Chronic Disease; Dexamethasone; Glucocorticoids; Infant, Premature
PubMed: 37606507
DOI: 10.1515/jpm-2023-0297 -
Journal of Experimental & Clinical... Jan 2022Multiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex...
BACKGROUND
Multiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM.
METHODS
Using MM cell lines and primary MM samples from relapsing MM patients, we evaluated the effects of knockdown of SUMO E1 (SAE2) or using TAK-981, a novel and specific SUMO E1 inhibitor, on Dex sensitivity. Xenograft mouse models were generated to determine the in vivo anti-MM effects of TAK-981 as a single agent and in combination with Dex. miRNA-seq, RNA-seq and GSEA analysis were utilized for evaluating key factors mediating Dex resistance. Chromatin immunoprecipitation (ChIP) assay was performed to determine the binding occupancy of c-Myc on promoter region of miRs.
RESULTS
We observed a significant negative correlation between SUMO E1 (SAE2) expression and Dex sensitivity in primary MM samples. Knockdown of SAE2 or using TAK-981 significantly enhances myeloma sensitivity to Dex in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Dex combination has been validated using primary relapsing MM patient samples and xenograft mouse models. SUMOylation inhibition increased glucocorticoid receptor (GR) expression via downregulation miR-130b. Using RNA and microRNA sequencing, we identified miR-551b and miR-25 as important miRs mediating Dex resistance in MM. Overexpression of miR-551b and miR-25 caused resistance to Dex, however, knockdown of miR-551b and miR-25 significantly enhanced Dex sensitivity in MM. SAE2 knockdown or TAK-981 treatment downregulated the expression of miR-551b and miR-25, leading to induction of miR targets ZFP36, ULK1 and p27, resulting in apoptosis and autophagy. We demonstrated c-Myc as a major transcriptional activator of miR-130b, miR-551b and miR-25 and SUMOylation inhibition downregulates these miRs level by decreasing c-Myc level.
CONCLUSION
Our study proves SUMOylation plays a crucial role in Dex resistance in MM and SUMOylation inhibition appears to be an attractive strategy to advance to the clinic for MM patients.
Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Disease Models, Animal; Humans; Mice; Multiple Myeloma; Sumoylation; Transfection; Xenograft Model Antitumor Assays
PubMed: 34983615
DOI: 10.1186/s13046-021-02226-9 -
European Cells & Materials Nov 2019While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of... (Review)
Review
While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of potentially harmful side effects at the molecular, cellular and tissue levels. One member of the glucocorticoid family, dexamethasone (DEX) has recently been demonstrated to rescue cartilage matrix loss and chondrocyte viability in animal studies and cartilage explant models of tissue injury and post-traumatic osteoarthritis, suggesting the possibility of DEX as a disease-modifying drug if used appropriately. However, the literature on the effects of DEX on cartilage reveals conflicting results on the drug's safety, depending on the dose and duration of DEX exposure as well as the model system used. Overall, DEX has been shown to protect against arthritis-related changes in cartilage structure and function, including matrix loss, inflammation and cartilage viability. These beneficial effects are not always observed in model systems using initially healthy cartilage or isolated chondrocytes, where many studies have reported significant increases in chondrocyte apoptosis. It is crucially important to understand under what conditions DEX may be beneficial or harmful to cartilage and other joint tissues and to determine potential for safe use of this glucocorticoid in the clinic as a disease-modifying drug.
Topics: Animals; Apoptosis; Arthritis; Cartilage; Dexamethasone; Glucocorticoids; Humans
PubMed: 31755076
DOI: 10.22203/eCM.v038a17