Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells.

PURPOSE: The goal of this study was to characterize the relationship between ATR and STAT3 interactions in human multiple myeloma (MM) cells. METHODS: Various MM cell lines, including IL-6-dependent cells were exposed to ATR inhibitors and effects on STAT3 Tyr705 and Ser727 were monitored by WB analysis and ImageStream analysis. Parallel studies examined induction of cell death, STAT3 DNA binding activity, and expression of STAT3 downstream targets (BCL-XL, MCL-1, c-MYC). Validation was obtained in ATR shRNA knock-down cells, and in cells ectopically expressing BCL-XL, MCL-1, or c-MYC. Analogous studies were performed in primary MM cells and in a MM xenograft model. RESULTS: Multiple pharmacologic ATR inhibitors inhibited STAT3 Tyr705 (but not Ser727) phosphorylation at low uM concentrations and down-regulated BCL-XL, MCL-1, c-MYC in association with cell death induction. Compatible results were observed in ATR shRNA knock-down cells. Cell death induced by ATR inhibitors was significantly attenuated in cells ectopically expressing constitutively active STAT3, BCL-XL, MCL-1, or c-MYC. Concordant results were observed in primary human MM cells and in an in vivo MM xenograft model. CONCLUSIONS: Collectively, these findings argue for a non-canonical role for the ATR kinase in STAT3 activation in MM cells, and suggest that STAT3 inactivation contributes to the lethal actions of ATR inhibitors in MM.

Evaluating the Therapeutic Potential of Idecabtagene Vicleucel in the Treatment of Multiple Myeloma: Evidence to Date.

Over the past two decades, significant progress has been made in the diagnosis, risk assessment and treatment of patients with multiple myeloma, translating into remarkable improvements in survival outcomes. Yet, cure remains elusive, and almost all patients eventually experience relapse, particularly those with high-risk and refractory disease. Immune-based approaches have emerged as highly effective therapeutic options that have heralded a new era in the treatment of multiple myeloma. Idecabtagene vicleucel (ide-cel) is one such therapy that employs the use of genetically modified autologous T-cells to redirect immune activation in a tumor-directed fashion. It has yielded impressive responses even in patients with poor-risk disease and is the first chimeric antigen receptor (CAR) T-cell therapy to be approved for treatment in relapsed or refractory multiple myeloma. In this review, we examine the design and pharmacokinetics of ide-cel, audit evidence that led to its incorporation into the current treatment paradigm and provide insight into its clinical utilization with a focus on real-life intricacies.

Smoldering multiple myeloma - Past, present, and future.

Smoldering multiple myeloma (SMM) routinely precedes the development of multiple myeloma. While some patients experience aggressive disease, others have more indolent courses akin to those with monoclonal gammopathy of undetermined significance. Much effort has been made to understand the pathobiological basis of this heterogeneity. Scientific advancements have led to the emergence of various clinical and genomic markers of relevance, translating into evolution of disease definitions over time. More recently, the interest in manipulation of biological pathways has intensified in a bid to stall or halt disease progression. Studies with lenalidomide have exemplified the promise of early intervention, whereas numerous therapeutic approaches remain the subject of ongoing clinical investigation. This review summarizes the historic progress made in defining SMM as a distinct clinicopathologic entity, provides a critical appraisal of the evidence guiding risk assessment, and suggests a pragmatic approach to its modern-day management. Finally, an overview of developments on the horizon is also provided.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5 mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥50 compared to baseline and sustained for 48 h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, secondary infections, duration of supplemental oxygen support, and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953 ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. IP-10 and CXCL-9 declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, P-value 0.0006). INTERPRETATION: Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-α antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN- γ , TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). INTERPRETATION: Consistent with a pathophysiological role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences.

Factors associated with bleeding events in patients on rivaroxaban for non-valvular atrial fibrillation: A real-world experience.

BACKGROUND: Rivaroxaban is a direct oral anticoagulant (DOAC) approved for the treatment of non-valvular atrial fibrillation (NVAF). Data related to the risk factors associated with rivaroxaban-induced bleeding in patients with NVAF remain scarce in the community setting. We sought to investigate these bleeding risk factors in a racially diverse patient population. METHODS: We conducted a single-center, retrospective study based on a chart review of patients who received rivaroxaban from our outpatient pharmacy from January 2015 to April 2018 for NVAF. Any reported bleeding event (BE) was recorded as either major or minor bleeding event. Demographic and clinical data were collected and analyzed. RESULTS: Of the 327 patients included in our analysis, 105 (32%) were female, and the mean age was 62 ± 12 years. Among the included patients, 176 (54%) patients were black, 71 (22%) were white, 51 (15.6%) were Hispanic, 13 (4%) were Asian, and 15 (4.6%) belonged to other races. 89 (27.2%) of the patients had co-prescription of aspirin. A total of 24 (7.3%) patients developed BE, out of which 9 (2.7%) patients had a major BE, and 15 (4.5%) patients had minor BE. Non-fatal gastrointestinal bleeding and epistaxis were the most common type of BE. On multivariable analysis, concurrent aspirin use (81 to 325 mg) (P = 0.03; odds ratio (OR) 2.60 [1.08-6.28]) and increasing age (P = 0.00; OR 1.06 [1.01-1.11]) were independent predictors of BE. CONCLUSION: In community practice, aspirin co-prescription is common among NVAF patients prescribed rivaroxaban. Increasing age and concurrent aspirin use are independent predictors of BE.