Low-dose Dexamethasone Treatment Research Articles

The effect of dexamethasone on functional pain following Transoral Robotic Surgery: a randomized double blinded clinical trial

Background Pain is prevalent after most TransOral Robotic Surgery (TORS) procedures and may limit function i.e. swallowing. Currently, there is limited knowledge regarding optimal pain treatment in TORS. Aims/objectives This clinical trial randomized patients to either a high-dose dexamethasone or low-dose dexamethasone treatment in addition to a multimodal basic analgesic protocol. The aim of the trial was to investigate the pain intensity during rest and swallowing using the Visual Analogue Scale (VAS) after TORS lingual tonsillectomy. Secondary outcomes were acceptable food consistency, nausea, vomiting, opioid rescue usage, length of hospitalization, feeding tube placements, readmissions, blood glucose levels and postoperative complications. Methods The trial was conducted between August 2020 and October 2022. Eligible patients were patients scheduled for TORS-L treatment of obstructive sleep apnea syndrome or as part of the diagnostic work-up of head and neck carcinoma of unknown primary. Results Eighteen patients were and randomized 1:1. There were overall no significant differences between groups in the reported VAS scores during rest or swallowing (p ≥ .05). Overall, there were no differences in the secondary outcomes. Conclusion There were no differences in the pain intensity in the two treatment groups allocated to a basic multimodal analgesic package and either high-dose dexamethasone or low-dose dexamethasone treatment. The trial is the first RCT to include pain measurement during a procedure-relevant activity, thus creating a platform for future recovery studies.

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis.

Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb. Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.

Changes in immune cell populations following KappaMab, lenalidomide and low-dose dexamethasone treatment in multiple myeloma.

Lenalidomide (LEN) is used to treat multiple myeloma (MM) and shows in vitro synergy with KappaMab (KM), a chimeric antibody specific for Kappa Myeloma antigen, an antigen exclusively expressed on the surface of kappa-restricted MM cells. Lenalidomide, dexamethasone (DEX) and KM control MM via multiple immunomodulatory mechanisms; however, there are several additional effects of the drug combination on immune cells. Lenalidomide can increase T cell and NKT cell cytotoxicity and dendritic cell (DC) activation in vitro. We investigated the immune cell populations in bone marrow of patients treated with KM, LEN and low-dose DEX in kappa-restricted relapsed/refractory MM ex vivo and assessed association of those changes with patient outcome. A cohort (n = 40) of patients with kappa-restricted relapsed/refractory MM, treated with KM, LEN and low-dose DEX, was analysed using a mass cytometry panel that allowed identification of immune cell subsets. Clustering analyses were used to determine significant changes in immune cell populations at time periods after treatment. We found changes in five DC and 17 T-cell populations throughout treatment. We showed an increase in activated conventional DC populations, a decrease in immature/precursor DC populations, a decrease in activated CD4 T cells and an increase in effector-memory CD4 T cells and effector CD8 T cells, indicating an activated immune response. These data characterise the effects of LEN, DEX, and KM treatment on non-target immune cells in MM. Treatment may support destruction of MM cells by both direct action and indirect mechanisms via immune cells.

Low-Dose and Short-Course Dexamethasone Treatment as a New Therapy against the Post-Embolization Syndrome after Transcatheter Arterial Chemoembolization in Primary Liver Cancer: A Retrospective Case-Control Study

Objective: Dexamethasone (DEX) is considered an effective treatment for Post-Embolization Syndrome (PES). However, the current commonly used DEX treatment course is long and involves a large amount of DEX and thus causes substantial side effects. This study aimed to evaluate the efficacy and safety of low-dose shortcourse DEX treatment in the prevention of PES to establish a new treatment course. Methods: A retrospective cohort study was conducted to observe the efficacy of DEX in treating PES on patients with primary liver cancer who underwent Transcatheter Arterial Chemoembolization (TACE). DEX was selected according to the wishes of the patients, who were subsequently divided into two groups. In the experimental group, 52 patients daily received an intravenous injection of 5 mg DEX and 5 mg tropisetron, starting on the day of TACE. The remaining 52 patients (control group) were treated with only 5 mg tropisetron daily. Incidence and degree of vomiting, abdominal pain, and fever were recorded. Routine blood tests and the C-Reactive Protein (CRP) test were performed, liver and kidney functions were evaluated, and the coagulation index and Eastern Cooperative Oncology Group (ECOG) performance status were assessed before and after TACE. Results: Severity scores of adverse reactions, such as vomiting, fever, and abdominal pain; incidence of grade 2 and 3 adverse reactions; and CRP and ECOG scores were significantly lower in the experimental group than in the control group (P< 0.05). There was no significant difference in routine blood parameters, liver and kidney functions, or coagulation between the two groups before or after TACE (P> 0.05). Conclusion: Low-dose and short-course DEX treatment after TACE can effectively reduce the severity of PES without side effects.

Therapeutic Effect of Corticosteroids for Critical COVID-19 Patients

The rapid spread of severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection has resulted in an unprecedented public health, economic, and social crisis worldwide. As therapeutics that can effectively clear the virus and terminate transmission are not available, supportive therapeutics are the main clinical methods for Corona Virus Disease (COVID-19) including corticosteroids, respiratory support, and extracorporeal membrane oxygenation for salvage therapy, while subsequent agents and vaccine candidates are still under investigation. COVID-19 is a two-phase disease: in the early phase, the pathology of the virus dominates; in the later phase, Immunopathology drives the disease. Low-dose dexamethasone treatment suppresses COVID-19-related Immunopathology by complementing endogenous cortisol activity, while avoiding the adverse effects of high-dose glucocorticoids therapy. Corticosteroids, as one of the main means of anti-inflammatory adjuvant, are controversial about its role in the treatment of COVID-19. Here, we retrospectively evaluate the therapeutic effect of corticosteroids by comparing the clinical data of patients with or without corticosteroids therapy at different severity level.

Correlative Analyses of Cereblon (CRBN), cMYC, IRF4, BLIMP1, and XBP1 with Clinical Outcomes in Stratus (MM-010), a Phase 3b Study of Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Correlative Analyses of Cereblon (CRBN), cMYC, IRF4, BLIMP1, and XBP1 with Clinical Outcomes in Stratus (MM-010), a Phase 3b Study of Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Impact of depression on adherence to lenalidomide plus low-dose dexamethasone in patients with relapsed or refractory myeloma.

While continued lenalidomide and low-dose dexamethasone (Rd) treatment could improve survival outcomes for multiple myeloma (MM), the association of depression on the adherence to Rd regimen in myeloma patients has never been studied even though depression is a common symptom among MM patients. This study aims to evaluate the impact of depression prior to Rd treatment on adherence to the treatment among patients with MM. This multicenter cohort study was conducted from January 2015 to October 2018 at five tertiary hospitals in Korea. Patients who completed fewer than 4cycles, 4-11cycles, and more than 12cycles were categorized as the poor adherence group (PAG), moderate adherence group (MAG), and good adherence group (GAG), respectively. Among141 patients, 41.8% of them had depression before beginning Rd treatment and 46% of participants were in the GAG. Compared with patients in the GAG (30.3%), patients in the PAG were more likely to have depression at baseline (90.0%) and had the higher distress scores (6.35 vs. 4.28, P < 0.01). Presence of depression prior to Rd treatment was significantly associated with poor adherence (IRR = 6.67, 95% CI = 1.45, 30.61) after adjusting for age, sex, education, ECOG, ISS stage, number of previous treatments, and disease status prior to Rd treatment. Patients with depression had a substantially high risk of poor adherence compared to patients without depression. Given that Rd treatment is mainly offered by outpatient clinics, active interventions to reduce depression should be considered for MM patients prior to Rd treatment.

Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2.

ObjectiveOur previous study showed that the combination therapy with atorvastatin and low-dose dexamethasone protected endothelial cell function in chronic subdural hematoma (CSDH) injury. In this study, we aimed to investigate the mechanism underlying the effects of this combination therapy on CSDH-induced cell dysfunction.MethodsMonocytes and endothelial cells were cocultured with CSDH patient hematoma samples to mimic the pathological microenvironment of CSDH. Monocytes (THP-1 cells) and endothelial cells (hCMEC/D3 cells) were cocultured in a transwell system for 24 h before stimulation with hematoma samples diluted in endothelial cell medium (ECM) at a 1:1 ratio. Tight junction markers were detected by Western blotting, PCR and immunofluorescence. hCMEC/D3 cells were collected for Western blot and PCR analyses to detect changes in the expression levels of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and Kruppel-like factor 2 (KLF-2). The IL-6, IL-10 and VEGF levels in the supernatant were measured by enzyme-linked immunosorbent assay (ELISA).ResultsKLF-2 expression in endothelial cells was decreased after stimulation with CSDH patient hematoma samples, but combination therapy with atorvastatin and low-dose dexamethasone reversed this trend. KLF-2 protected injured cells by increasing the expression of VE-cadherin and ZO-1; attenuating the expression of VCAM-1, ICAM-1, IL-6 and VEGF; and enhancing the expression of IL-10, all of which play pivotal roles in endothelial inflammation. Moreover, the effect of combination therapy with atorvastatin and low-dose dexamethasone was obviously reduced in endothelial cells with KLF-2 knockdown compared with normal cells.ConclusionCoculture with hematoma samples decreased KLF-2 expression in human cerebral endothelial cells. Combination therapy with atorvastatin and low-dose dexamethasone counteracted hematoma-induced KLF-2 suppression in human cerebral endothelial cells to attenuate robust endothelial inflammation and permeability. KLF-2 plays an important role in drug therapy for CSDH and may become the key factor in treatment and prognosis.

Influence of Immune Status on the Airborne Colonization of Piglets with Methicillin-Resistant Staphylococcus aureus (MRSA) Clonal Complex (CC) 398.

Colonized vertebrates including humans and pigs are to date the main reservoirs of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA). Currently, the mechanisms underlying colonization of pigs are not fully understood.We investigated the influence of piglet pre-immune status on airborne MRSA colonization. Three groups of MRSA-negative piglets were primed and exposed to airborne LA-MRSA (104 colony forming units (cfu)/m3) in an aerosol chamber for 24 h. One group was treated intramuscularly with dexamethasone (1 mg/kg body weight) to imitate weaning stress. The second group was exposed to bacterial endotoxin containing MRSA aerosol. Both conditions play a role in the development of multifactorial diseases and may promote MRSA colonization success. The third group served as control.The piglets' MRSA status was monitored for 21 days via swab samples. At necropsy, specific tissues and organs were analyzed. Blood was collected to examine specific immunological parameters.The duration of MRSA colonization was not extended in both treated groups compared to the control group, indicating the two immune-status influencing factors do not promote MRSA colonization. Blood sample analysis confirmed a mild dexamethasone-induced immune suppression and typical endotoxin-related changes in peripheral blood. Of note, the low-dose dexamethasone treatment showed a trend of increased MRSA clearance.

Lose-Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress-Deprived Joint Injury Explant Model.

Secondary joint damage is the process by which a single injury can lead to detrimental changes in adjacent tissue structures, typically through the spread of inflammatory responses. We recently developed an in vitro model of secondary joint damage using a murine rotator cuff explant system, in which injuries to muscle and bone cause massive cell death in otherwise uninjured tendon. The purpose of the present study was to test the ability cytokine-targeted and broad-spectrum therapeutics to prevent cell death and tissue degeneration associated with secondary joint damage. We treated injured bone-tendon-muscle explants with either interleukin-1 receptor antagonist, etanercept, or dexamethasone (DEX) for up to 7 days in culture. Only the low-dose DEX treatment was able to prevent cell death and tissue degeneration. We then identified a critical window between 24 and 72 h following injury for maximal benefit of DEX treatment through timed administration experiments. Finally, we performed two tendon-only explant studies to identify mechanistic effects on tendon health. Interestingly, DEX did not prevent cell death and degeneration in a model of cytokine-induced damage, suggesting other targets of DEX activity. Future studies will aim to identify factors in joint inflammation that may be targeted by DEX treatment, as well as to investigate novel delivery strategies. Statement of clinical significance: Overall, this work demonstrates beneficial effects of DEX administration on preventing tenocyte death and extracellular matrix degeneration in an explant model of secondary joint damage, supporting the clinical use of low-dose glucocorticoids for short-term treatment of joint inflammation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:139-149, 2020.

PB2117 POMALIDOMIDE PLUS LOW‐DEXAMETHASONE TREATMENT FOR ≥ 1 YEAR IN PATIENTS WITH RELAPSED REFRACTORY MULTIPLE MYELOMA AND RENAL IMPAIRMENT: A SUBANALYSIS OF THE MM‐013 PHASE 2 STUDY

Background:The combination of the immunomodulatory agent pomalidomide (POM) and dexamethasone (DEX) is approved in the European Union for patients (pts) with relapsed refractory multiple myeloma (RRMM), including those with renal impairment (RI). The MM‐013 (NCT02045017; EudraCT Number: 2013‐001903‐36) phase 2, noncomparative trial has demonstrated a benefit with POM + low‐dose dexamethasone (LoDEX) in pts with moderate RI, severe RI, and severe RI requiring hemodialysis (Dimopoulos M, et al. J Clin Oncol. 2018;36:2035‐2043.)Aims:To report efficacy and safety of ≥ 1 year of POM + LoDEX treatment (Tx) in RRMM pts with moderate or severe RI, including those on hemodialysis.MethodsThe study enrolled 3 cohorts: (A, n = 33)–moderate RI (estimated glomerular filtration rate [eGFR] 30 to &lt; 45 mL/min/1.73 m2), (B, n = 34)–severe RI (eGFR &lt; 30 mL/min/1.73 m2), and (C, n = 14)–severe RI requiring hemodialysis. Pts received 28‐day cycles of POM (4 mg/day on days 1 to 21) and LoDEX (40 mg/day; 20 mg/day if age &gt; 75 yrs, on days 1, 8, 15, and 22). All pts must have received ≥ 1 prior Tx including lenalidomide and progressed during or after their last anti‐myeloma therapy before entering the study. Primary endpoint was overall response rate (ORR). All pts provided informed consent.Results:A total of 17 pts (21.0%) of 81 pts enrolled in this trial, received Tx for ≥ 1 year: 10 in cohort A, 6 in cohort B, and 1 in cohort C, of whom 2, 2, and 1 pt, respectively were still on Tx as of January 4, 2019. Overall, 12 pts (70.6%) discontinued Tx; 7 (41.2%) due to progressive disease, 3 (17.6%) due to adverse events (AEs), and 1 pt (5.9%) each due to death and withdrawal from Tx. Median age was 68 yrs (range, 55–86 yrs) and 64.7% of pts were male. Median number of prior lines of Tx was 3, 2, and 4 in cohorts A, B, and C, respectively. Median Tx duration was 19.8, 19.9, and 32.3 mos and median dose intensity was 4.1, 3.7, and 4.9 mg. Median modification of diet in renal disease eGFR was 40.6, 18.0, and 4.0 mL/min/1.73m2. Response rates are shown in Table 1. Median time to response was 1.4, 1.9, and 2.9 mos in cohorts A, B, and C, respectively. Median duration of response (DOR) was 14.7 mos for the 7 pts who progressed in cohort A. DOR was not estimable (NE) for the two other cohorts as 1 pt progressed in cohort B and the pt in cohort C was still on Tx. Renal response was 30.0%, 50.0%, and 0% (Table 1). Overall, median progression‐free survival was 25.8 mos (95% CI, 14.5‐NE). The most frequent grade 3/4 adverse events were neutropenia (6, 1, and 1 pt in cohorts A, B, and C, respectively), anemia (3, 3, and 1 pt), and infections (6, 2, and 1 pt). One pt in cohort A discontinued POM due to ≥ 1 AE. AE‐related POM dose reductions occurred in 3 and 2 pts in cohorts A and B, respectively. AE‐related POM dose interruptions occurred in 7, 6, and 1 pt in cohorts A, B, and C, respectively.Summary/Conclusion:This ongoing, noncomparative study confirms that Tx with POM + LoDEX is efficacious in RRMM pts with RI and can be tolerated for ≥ 1 year.image

Short-term dexamethasone plus acetylsalicylic acid treatment during in vitro fertilization procedure.

Embryo implantation represents the major limiting step during in vitro fertilization (IVF) procedure. Immu- nological and coagulation abnormalities were shown to have a substantial part in multifactorial etiology of IVF failure. We aimed to investigate the effect of short-term low-dose dexamethasone plus acetylsalicylic acid (ASA) treatment, starting at the time of embryo transfer, on the implantation and clinical pregnancy rates in general IVF population. Out of 233 consecutive patients undergoing fresh IVF/intracytoplasmic sperm injection (ICSI) cycles 64 received an adjuvant treatment consisting of dexamethasone (0.5 mg/day) plus ASA (100 mg/day) (DA group), starting on the day of embryo transfer. Patients not receiving these medications comprised a control group. Significantly more patients in DA group had positive ß-hCG values than controls (59.38% vs. 37.67%, p = 0.004) (OR = 2.42, 95% CI: 1.33-4.41). Implantation rate was 26.53% in DA group and 15.92% in controls (p = 0.0294). Clinical preg- nancy rate per started cycle was higher in DA group (43.59%) than controls (28.92%), but the difference was not significant (p = 0.0879; OR = 1.99, 95% CI: 0.89-4.41). Our study shows a potential benefit of dexamethasone plus ASA adjuvant treatment in females undergoing IVF/ICSI procedure. As these results show improvement of IVF outcome, a greater number of patients undergoing this type and regime of adjuvant treatment should be investigated.

The use of dexamethasone in animals: implication for fertility, pregnancy and extrapolation of the animal data to humans

Exposure to dexamethasone causes numerous changes in various biological systems including the reproductive system and this has huge implication on fertility and pregnancy. Maternal dexamethasone administration promotes foetal lung maturation and thermoregulation in premature foetuses. This indication makes dexamethasone a drug of choice in maternal and neonatal human and veterinary health care. In addition, dexamethasone is widely used in human and veterinary medicine as potent anti-inflammatory, immunosuppressive and analgesic drug in all age categories. Although the safety profile of short term dexamethasone treatment has been established, there has been growing concern about the long term effects of dexamethasone therapy and its implication on fertility and pregnancy in animals and humans. Most of the indications or uses in humans are extrapolated from animal data. This necessitates the need to provide review updates of current literature on dexamethasone use in humans and animals as there are many intrinsic differences between humans and animals. The review provides an overview of dexamethasone uses, its merits and demerits on animal pregnancy and fertility and implication on extrapolation of the animal data to humans. The review is based on a comprehensive literature search of relevant materials between 1969 and 2016 as well as authors’ personal manuscript/abstract files and citations of known references and discussed according to the multidisciplinary clinical experience of the authors. Although low-dose dexamethasone treatment has been used in veterinary and human clinics for many years and produced no severe effect on vital functions, repetitive high dose or long-term therapy may be associated with more serious sequelae on fertility and pregnancy. While no animal truly recapitulates human pregnancy and fertility, it is recommended that results from animal data be subjected to rigorous preclinical pharmacokinetic scaling processes to justify possible extrapolation to humans. Keywords: Animals, Dexamethasone, Fertility, Humans, Pregnancy

ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T

BackgroundAtaxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.ResultsIn the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new “ATMdexa1 variants” originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients’ blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.ConclusionsFor the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.

Low Frequency of CD161+CD4+ T Cells Correlate with the Occurrence of Infections in Refractory/Relapsed Multiple Myeloma Patients Receiving Lenalidomide Plus Low-Dose Dexamethasone Treatment

Background Although the combination of lenalidomide and low-dose dexamethasone (Len-dex) is known to preserve the efficacy with reduced toxicity than lenalidomide plus high-dose dexamethasone (Len-Dex) in patients with refractory/relapsed multiple myeloma (RRMM), infection is still a leading toxicity. Moreover, the patterns and risks for infection in patients with RRMM during Len-dex treatment remain unclear and there is a need to identify contributing factors associated with increased risk for infection. Considering the disease-related and treatment-related immune deficits in patients with RRMM, we explored the predictive implications of the revelation of the immune cell populations prior to Len-dex initiation for the occurrence of infection. In addition, the various clinical and laboratory parameters were analyzed. Methods Clinical and microbiology records of 90 RRMM patients during Len-dex treatment were reviewed and risk factors for infection were analyzed using the logistic regression. In addition, to develop the new immune cell biomarker, we prospectively examined immune cell populations (CD3, CD4CD161, CD8CD161, Lin-HLA-DR-CD11b+CD33+, CD14+HLA-DR-, NK and NKT cells) of the peripheral blood taken on baseline of Len-dex therapy. Results Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). During a median 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown focus. Severe episodes were frequently observed during early 3 cycles. In the univariate analyses, lower Hb ( + CD161 + cells in peripheral blood prior to Len-dex were associated with the occurrence of infection, especially during early 3 cycles of Len-dex therapy. Conclusions We demonstrated several clinical predictive factors for the occurrence of infection in patients with RRMM receiving Len-dex treatment. And we found that the frequency and absolute count of CD4 + CD161 + cells may provide additional information for predicting the occurrence of infection in early period of Len/dex therapy. Disclosures No relevant conflicts of interest to declare.

Low Frequency of CD161+CD4+ T Cells Correlate with the Occurrence of Infections in Refractory/Relapsed Multiple Myeloma Patients Receiving Lenalidomide Plus Low-Dose Dexamethasone Treatment

Background Although the combination of lenalidomide and low-dose dexamethasone (Len-dex) is known to preserve the efficacy with reduced toxicity than lenalidomide plus high-dose dexamethasone (Len-Dex) in patients with refractory/relapsed multiple myeloma (RRMM), infection is still a leading toxicity. Moreover, the patterns and risks for infection in patients with RRMM during Len-dex treatment remain unclear and there is a need to identify contributing factors associated with increased risk for infection. Considering the disease-related and treatment-related immune deficits in patients with RRMM, we explored the predictive implications of the revelation of the immune cell populations prior to Len-dex initiation for the occurrence of infection. In addition, the various clinical and laboratory parameters were analyzed.Methods Clinical and microbiology records of 90 RRMM patients during Len-dex treatment were reviewed and risk factors for infection were analyzed using the logistic regression. In addition, to develop the new immune cell biomarker, we prospectively examined immune cell populations (CD3, CD4CD161, CD8CD161, Lin-HLA-DR-CD11b+CD33+, CD14+HLA-DR-, NK and NKT cells) of the peripheral blood taken on baseline of Len-dex therapy.Results Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). During a median 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown focus. Severe episodes were frequently observed during early 3 cycles. In the univariate analyses, lower Hb (<10 g/dL) and serum albumin (<3.5 mg/dL), and higher serum creatinine (≥2 mg/dL) were associated with increased risk of infections (≥grade 3) during early 3 cycles. After adjusting for risk factors for infection on univariate analyses, multivariate analyses showed that lower Hb (<10 g/dL) was an independent factor for the occurrence of infections and lower frequency (P = 0.009) and absolute count (P = 0.072) of CD4+CD161+ cells in peripheral blood prior to Len-dex were associated with the occurrence of infection, especially during early 3 cycles of Len-dex therapy.Conclusions We demonstrated several clinical predictive factors for the occurrence of infection in patients with RRMM receiving Len-dex treatment. And we found that the frequency and absolute count of CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in early period of Len/dex therapy. DisclosuresNo relevant conflicts of interest to declare.

Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma.

Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.

Dexamethasone-induced acute excitotoxic cell death in the developing brain

There is substantial evidence that the use of glucocorticoids in neonates is associated with an increased risk of neurodevelopmental disorders. However, it remains unclear how treatment with low doses of dexamethasone (DEX) may result in behavioral abnormalities without evident signs of immediate neurotoxicity in the neonatal brain. It is possible that cells vulnerable to the pro-apoptotic effects of low doses of DEX escaped detection due to their small number in the developing brain. In agreement with this suggestion, low-dose DEX treatment (0.2mg/kg) failed to induce apoptosis in the cortex or hippocampus proper of neonatal rats. However, this treatment was capable of inducing apoptosis specifically in the dorsal subiculum via a two-step mechanism that involves glutamate excitotoxicity. Application of DEX leads to increased activity of CA1/CA3 hippocampal MAP2-positive neurons, as determined by c-Fos expression at 0.5–1h after DEX injection. Five hours later, the apoptotic markers (fragmented nuclei, active caspase-3 and TUNEL labeling) increased in the dorsal subiculum, which receives massive glutamatergic input from CA1 neurons. Pretreatment with memantine, an antagonist of glutamate NMDA receptors, dose dependently blocked the DEX-induced expression of apoptotic markers in the subicular neurons and astrocytes. These findings provide new insights into the mechanisms of DEX-induced neurotoxicity as well as on the mechanism of therapeutic action of antagonists of NMDA receptors against neurobehavioral disorders caused by neonatal exposure to glucocorticoids.

Impact of Lenalidomide Plus Low-Dose Dexamethasone Treatment on Immune Cell Populations of the Patients with Refractory/Relapsed Multiple Myeloma

Background: Lenalidomide combined with low-dose dexamethasone (Len-dex) is an effective treatment for the patients with refractory/relapsed multiple myeloma (RRMM). The anti-myeloma effect of lenalidomide is associated with activation of the immune system, but the exact immunomodulatory mechanisms in vivo and clinical impact of Len/dex in RRMM patients remains unclear. In this study, we analyzed immune cell populations in patients receiving Len-dex for the treatment of RRMM.Methods: Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len/dex therapy. CD3+, CD4+, CD8+, CD161+ T cells, natural killer (NK) cell (CD16+/CD56+), NKT-like cell (CD3+/CD56+) and myeloid-derived suppressor cell (MDSC) including granulocytic (G-MDSC) and monocytic (M-MDSC) were analyzed by flow cytometry. In addition, response was assessed in 81 patients receiving more than 4 cycles of Len-dex and the comparison of cell populations according to an achievement of ≥very good partial response (VGPR) was performed.Results: Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). At baseline, peripheral blood CD3+ cell frequency was 51.65 ± 1.79% which was significantly decreased to 41.67 ± 2.44% (P=0.001) and 39.72 ± 2.90% (P< 0.001) after 2 and 3 cycles of therapy, respectively. Frequency of both CD4+ cell and CD8+ cells was also significantly decreased by 3 cycles of therapy, while NK cell frequency was significantly increased after Len-dex treatment (P<0.05). For the T-cell subset, the frequency of CD8+ CD161high cells was significantly decreased (1.13 ± 0.16% at baseline to 0.65 ± 0.13% at post-3 cycles, P< 0.05), while no trend was observed in CD4+ CD161+ cell frequency. No significant change was observed in frequency of G-MDSC and M-MDSC after Len-dex. Among 81 evaluable patients, 36 patients obtained ≥VGPR and 45 ≤ partial response. After adjusting for factors affecting failure of achieving a response of ≥VGPR on univariate analyses, multivariate analyses showed that decrease in CD8+ cell frequency (P=0.043) and increase in M-MDSC frequency (P=0.033) by post-3 cycles of Len-dex treatment were predictors for failure of achieving ≥VGPR. High frequency of NKT-like cell prior to Len-dex treatment could predict a longer time to progression (RR of 0.40, P=0.011). In addition, patients with less decrease in frequency of both CD3+ cell and CD8+ cells by post-3 cycles had a longer time to next treatment (RR of 0.24, P=0.024 and RR of 0.33, P=0.044, respectively).Conclusion: Our data demonstrate that Len-dex therapy in patients with RRMM is associated with decreased frequency of T cells with a trend of increased NK cell frequency. Change in CD8+ cell and M-MDSC frequency can correlate with the quality of response to Len-dex. Baseline NKT-like cell frequency and change in CD3+ and CD8+ cells early after treatment may predict continuation of anti-myeloma effect of Len-dex therapy. DisclosuresNo relevant conflicts of interest to declare.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

Pomalidomide is a distinct oral IMiD(®) immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30.