Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. FUNDING: Genmab and AbbVie.

A novel method for analyzing genetic association with longitudinal phenotypes.

Knowledge of genes influencing longitudinal patterns may offer information about predicting disease progression. We developed a systematic procedure for testing association between SNP genotypes and longitudinal phenotypes. We evaluated false positive rates and statistical power to localize genes for disease progression. We used genome-wide SNP data from the Framingham Heart Study. With longitudinal data from two real studies unrelated to Framingham, we estimated three trajectory curves from each study. We performed simulations by randomly selecting 500 individuals. In each simulation replicate, we assigned each individual to one of the three trajectory groups based on the underlying hypothesis (null or alternative), and generated corresponding longitudinal data. Individual Bayesian posterior probabilities (BPPs) for belonging to a specific trajectory curve were estimated. These BPPs were treated as a quantitative trait and tested (using the Wald test) for genome-wide association. Empirical false positive rates and power were calculated. Our method maintained the expected false positive rate for all simulation models. Also, our method achieved high empirical power for most simulations. Our work presents a method for disease progression gene mapping. This method is potentially clinically significant as it may allow doctors to predict disease progression based on genotype and determine treatment accordingly.

Determination of differential cross sections and kinetic energy release of co-products from central sliced images in photo-initiated dynamic processes.

For photo-initiated inelastic and reactive collisions, dynamic information can be extracted from central sliced images of state-selected Newton spheres of product species. An analysis framework has been established to determine differential cross sections and the kinetic energy release of co-products from experimental images. When one of the reactants exhibits a high recoil speed in a photo-initiated dynamic process, the present theory can be employed to analyze central sliced images from ion imaging or three-dimensional sliced fluorescence imaging experiments. It is demonstrated that the differential cross section of a scattering process can be determined from the central sliced image by a double Legendre moment analysis, for either a fixed or continuously distributed recoil speeds in the center-of-mass reference frame. Simultaneous equations which lead to the determination of the kinetic energy release of co-products can be established from the second-order Legendre moment of the experimental image, as soon as the differential cross section is extracted. The intensity distribution of the central sliced image, along with its outer and inner ring sizes, provide all the clues to decipher the differential cross section and the kinetic energy release of co-products.

Three-dimensional sliced fluorescence imaging in bulbs.

To study dynamic behaviors of molecular photodissociation processes and photoinitiated inelastic and reactive collisions in a bulb environment, a three-dimensional sliced fluorescence imaging method has been developed. This experimental method combines the sliced fluorescence imaging techniques and a double resonance spectroscopic detection scheme to acquire the central slice of state-selected Newton spheres of scattering products. To illustrate the essence and simplicity of the present method, experimental images of state-selected CN photofragments from the ICN photodissociation are presented. For other chemically significant product species with a single fluorescent excited state, an infrared-optical double resonance detection scheme warrants the present technique a general method in the study of dynamic processes in bulbs.

Sliced fluorescence imaging: a versatile method to study photo-induced dynamic processes.

To reduce the image blurring which originates from contributions of a cylindrical array of photolysis events in a photo-induced experiment, a variant of fluorescence imaging techniques has been developed to study photodissociation dynamics and collisional relaxation processes in the bulk. The experimental arrangement utilizes sliced imaging techniques of photofragments by the laser-induced fluorescence detection scheme. An unconventional procedure is employed to guide the photolysis laser in the viewing direction of the imaging detector with an appropriate obstruction. The sliced image in the direction perpendicular to the photolysis laser is equivalent to a two-dimensional projection of the fluorescence image of photoproducts from a single photolysis center. Experimental images of state-selected CN photofragments from the ICN photodissociation are presented to illustrate the versatility of the present method.

Electronic angular momentum polarizations of photofragments: a case study of ICN photodissociation from a perpendicular transition.

A quantum treatment on ICN photodissociation from an initial perpendicular transition (Omega'=+/-1<--Omega"=0) to the asymptote CN(|Sigma+,J'M'N'1/2>)+I(2P3/2) is presented. Density matrices of both photofragments are derived and explicit expressions of the state multipoles in terms of the angular momentum coupling coefficients and the rotation-bending factors have been obtained. To perceive the physical origin of electronic angular momentum polarizations of the iodine photofragments, a correlation scheme which considers the magnetic dipolar and the electrostatic dipole-quadrupole interactions between I and CN cofragments is proposed. For ICN precursors in the vibrational ground state or in the equally populated l-type split levels, the alignment parameters of the iodine photofragments in the molecular frame can be calculated according to this long-range interaction model. For the perpendicular transition |1Pi1><--|1Sigma0+>, its alignment parameters of I(2P3/2) from the incoherent and coherent transitions to the |Omega'=1> and |Omega'=-1> components are rho(0)2(1Pi1)=0.756 and rho2(2)(1Pi1)=-0.656, respectively. For the perpendicular transition to |3Pi1>, rho(0)2(3Pi1)=-0.878 and rho2(2)(3Pi1)=0.328 are from the incoherent transition, whereas rho(0)2(3Pi1)=0.122 and rho2(2)(3Pi1)=0.328 are from the coherent transition. To analyze the photoion images of iodine photofragments, angular distributions of I+ from the 2+1 resonance-enhanced multiphoton ionization detection scheme are derived.

Utility of the auditory evoked potentials index as an indicator for endotracheal intubation.

BACKGROUND: The A-line ARX Index (AAI) has been used as an indicator of depth of anesthesia. The study examined whether AAI-guided endotracheal intubation (EI), compared with experience guidance, could provide better hemodynamic stability during general anesthesia (GA). METHODS: One hundred and four patients were included in this study. In the control group, EI was performed based on the judgment of the anesthesiologist by clinical experience. In the study groups, EI was performed at an AAI value of either 15, 20, or 30. GA was induced with cisatracurium, lidocaine, fentanyl, thiamylal and succinylcholine. Heart rate (HR) and mean arterial pressure (MAP) were recorded at baseline, 1 min before and 1 and 3 min after intubation. The change of hemodynamics over 20% in the space between 1 min before and after intubation was defined as severe change. RESULTS: The incidences of severe changes of HR and MAP in the AAI-15 and AAI-20 groups were significantly lower than those in the control group (19% and 39% vs. 68%, P < 0.01 and 0.05; 52% and 52% vs. 91%, P < 0.01, respectively). The induction time was significantly shorter in the control group than that in the study groups (183 +/- 47 vs. 366 +/- 151, 248 +/- 53, and 255 +/- 85 sec, P < 0.01). Highest dose of thiamylal and longest induction time were needed in the AAI-15 group. CONCLUSIONS: Compared with the routine clinical practice, AAI monitoring helps to achieve better condition for EI during induction with less hemodynamic changes. The AAI value of 20 is suggested as an optimal indicator for EI.