An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma

: Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered

Impact of Early Relapse within 24 Months after First-Line Systemic Therapy (POD24) on Outcomes in Patients with Marginal Zone Lymphoma: A US Multisite Study

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis

Graphene Nanoribbon-Based Platform for Highly Efficacious Nuclear Gene Delivery

Current efforts in the design and development of nonviral vectors for gene delivery and transfection have focused on the development of versatile agents that can load short or large sized genetic material, and are efficacious without eliciting toxicity in dividing and nondividing cells. Herein, we have investigated oxidized graphene nanoribbons (O-GNRs) as nonviral vectors for gene therapy and report in vitro studies that detail their cytotoxicity, intracellular and nuclear uptake, and gene delivery and transfection efficiencies. Our results indicate that, without additional functionalization with positively charged groups or other nonviral vectors, O-GNRs could load large amounts of small-sized single-stranded or large-sized double stranded genetic materials. O-GNRs at potential therapeutic doses (20–60 μg/mL) elicited lower cytotoxicity compared to widely used commercial nonviral gene delivery vectors (Polyethylenimine and Fugene 6). The O-GNR-plasmid DNA complexes showed uptake into vesicular structures of dividing Henrietta Lacks (HeLa) and nondividing Human umbilical vein endothelial cells (HUVEC), release into the cell’s cytoplasm and entry into the nucleus. In these cells, O-GNRs loaded with enhanced green fluorescence protein (EGFP) plasmid or siRNA against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) showed a concentration- and time- dependent increase in gene delivery and gene transfection efficiencies up to 96–98%. The results suggest that O-GNRs are promising candidates as versatile and efficient nonviral vectors of small- or large-sized genetic material in primary and secondary cell types for gene therapy

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Abstract Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates

Nanoparticle-Facilitated Membrane Depolarization-Induced Receptor Activation: Implications on Cellular Uptake and Drug Delivery

Cell-specific uptake of drug delivery systems (DDSs) are crucial to achieve optimal efficacy of many drugs. Widely employed strategies to facilitate targeted intracellular drug delivery involves attachment of targeting ligands (peptides or antibodies) to DDSs. Target receptors mutations can limit the effectiveness of this approach. Herein, we demonstrate, through in vitro inhibitory and drug delivery studies, that graphene nanoribbons (GNRs), water dispersed with the amphiphilic polymer called PEG-DSPE ((1, 2-distearoyl-<i>sn</i>-glycero-3-phosphoethanolamine-N [amino (polyethylene glycol)]) (induce membrane depolarization-mediated epidermal growth factor receptor (EGFR) activation. This phenomenon is ligand-independent and EGFR activation occurs via influx of Ca²⁺ ions from the extracellular space. We further provide evidence, through in vivo studies, that this mechanism could be exploited to facilitate efficacious drug delivery into tumors that overexpress EGFR. The results suggest that transient membrane depolarization-facilitated cell receptor activation can be employed as an alternate strategy for enhanced intracellular drug delivery

Passive Cavitation Mapping by Cavitation Source Localization from Aperture-Domain Signals - Part II: Phantom and in Vivo Experiments

Passive cavitation mapping (PCM) techniques typically utilize a time-exposure acoustic (TEA) approach, where the received radio frequency data are beamformed, squared, and integrated over time. Such PCM-TEA cavitation maps typically suffer from long-tail artifacts and poor axial resolution with pulse-echo diagnostic arrays. Here, we utilize a recently developed PCM technique based on cavitation source localization (CSL), which fits a hyperbolic function to the received cavitation wavefront. A filtering method based on the root-mean-square error (rmse) of the hyperbolic fit is utilized to filter out spurious signals. We apply a wavefront correction technique to the signals with poor fit quality to recover additional cavitation signals and improve cavitation localization. Validation of the PCM-CSL technique with rmse filtering and wavefront correction was conducted in experiments with a tissue-mimicking flow phantom and an in vivo mouse model of cancer. It is shown that the quality of the hyperbolic fit, necessary for the PCM-CSL, requires an rmse \u3c 0.05 mm2 in order to accurately localize the cavitation sources. A detailed study of the wavefront correction technique was carried out, and it was shown that, when applied to experiments with high noise and interference from multiple cavitating microbubbles, it was capable of effectively correcting noisy wavefronts without introducing spurious cavitation sources, thereby improving the quality of the PCM-CSL images. In phantom experiments, the PCM-CSL was capable of precisely localizing sources on the therapy beam axis and off-axis sources. In vivo cavitation experiments showed that PMC-CSL showed a significant improvement over PCM-TEA and yielded acceptable localization of cavitation signals in mice

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B&ndash;Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens