Citations

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter registrational trial of axi-cel in patients with refractory, aggressive B-cell non-Hodgkin lymphoma. In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with a 76% objective response rate and 47% complete response. The incidence of Grade 3 and higher (Gr 3+) cytokine release syndrome (CRS) and neurologic events (NE) was 13% and 29%, respectively, in 93 patients with 1 month follow-up (Neelapu ASH 2016). We present novel immune signatures of Gr 3+ CRS and NE by analyzing the axi-cel-related biomarker profile in association with clinical outcomes. Methods: In this interim analysis of 62 patients, 44 serum analytes pre- and post-axi-cel treatment were measured via ELISA at multiple timepoints during the first month. The number of CAR+ cells in blood was determined by qPCR. Kinetics and association of these markers with CRS and NE were analyzed. The treatment-related profile was defined by analytes with at least double an increase over baseline in at least 50% of patients. These analytes were selected and evaluated for association with Gr 3+ CRS or NE. Immune signatures were determined based on p-values applied to peak or cumulative levels of analytes and adjusted for multiplicity (stepdown method). Results: Out of 44 analytes measured, 12 demonstrated an increase by double over baseline in at least 50% of patients. This axi-cel-related biomarker profile includes immune proliferative/modulating cytokines, pro-inflammatory cytokines, markers of myeloid activation, and chemokines. Markers with the highest median-fold increase were IFNγ (44x), IL-10 (31x), IL-6 (26x), IL-15 (20x), and GRZB (17x). These peaked within 7-14 days and generally returned to baseline within 1 month post-treatment. Within this panel of 12 analytes elevated post-axi-cel treatment, markers associated with Gr 3+ CRS (p<0.05) were IL-10, IL-6, IL-2Rα, IL-8, MCP-1, IFNγ, IL-1Rα, and IP-10. Markers associated with Gr 3+ NE (p<0.05) were IL-6, IL-15, IL-8, and MCP-1. Peak levels of CAR T cells in blood, occurring within 14 days post-infusion, were associated with Gr 3+ NE (p=0.02) but not Gr 3+ CRS (p=0.6). A majority of patients with Gr 3+ NE had only Gr 0-2 CRS (16/22) while nearly 50% of patients with Gr 3+ CRS had Gr 0-2 NE (5/11). Conclusions: Biomarker and clinical evaluation suggests mechanistic differences underlying CRS and NE following axi-cel treatment. While Gr 3+ NE was associated with CAR T cell expansion, Gr 3+ CRS was instead associated with a broader array of serum markers, many linked to systemic myeloid activation. Further understanding of these immune signatures may provide insight into managing AEs associated with anti-CD19 CAR T cell therapy. Citation Format: Frederick L. Locke, John Rossi, Xiaodong Xue, Sattva S. Neelapu, Daniel H. Ryan, Armin Ghobadi, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick M. Reagan, Marika Sherman, Janice Nagatani, Xiao Zhang, Lynn Navale, William Y. Go, Jeff Wiezorek, Adrian Bot. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT020. doi:10.1158/1538-7445.AM2017-CT020

Objective: To report the clinical features, treatment, and outcomes of patients with immune checkpoint inhibitor-induced hepatotoxicity. Patients and Methods: In this retrospective observational study, we identified patients with metastatic malignant melanoma seen in consultation and/or treated between March 2011 and March 2016. Hepatotoxicity was assessed using the Common Terminology Criteria for Adverse Events, v4.0. Results: Seventeen patients were identified as having any degree of hepatotoxicity by history (grade 1 to 4). Twelve of 17 were diagnosed after ipilimumab, 3 of 17 were diagnosed after pembrolizumab, and 2 of 17 after ipilimumab combined with nivolumab. Median time from first dose of immune therapy to hepatotoxicity was 52 days. Clinical symptoms were variable: asymptomatic, fatigue, myalgias, headache, abdominal pain, nausea, vomiting, confusion, and/or jaundice. Eight patients had concurrent adverse events including colitis, hypophysitis, pneumonitis, and/or rash. Immune therapy was discontinued in all patients except 3. The patients were most commonly treated with systemic corticosteroids such as prednisone. Immunosuppression was discontinued by taper over a median of 42 days; in 3 patients steroids had to be reinitiated based on clinical or laboratory worsening of liver tests. Normalization of liver tests was seen within a median of 31 days of immunosuppression initiation. One patient with grade 4 hepatotoxicity had normalization with the addition of cyclosporine. Conclusions: Melanoma patients treated with immune checkpoint inhibitors should be monitored regularly for hepatotoxicity. Treatment with discontinuation of therapy and initiation of corticosteroids is indicated with grade 3 or 4 hepatotoxicity. Cyclosporine may be beneficial in steroid-refractory hepatotoxicity.

ObjectivesLeft ventricular (LV) septal hypertrophy in aortic stenosis raises diagnostic and therapeutic questions. However, the etiology and clinical consequences of this finding have not been well studied. The aim of this study was to perform a morphologic evaluation of the LV in aortic stenosis and to investigate the contributing factors and consequences of septal hypertrophy.MethodsPatients with moderate or severe aortic stenosis were prospectively enrolled. Patients with previous myocardial infarction, wall motion abnormalities, at least moderate valvular regurgitation, known cardiomyopathy, an LV ejection fraction of less than 50%, and age younger than 65 years were excluded.ResultsForty‐one patients underwent a final analysis. Septal hypertrophy (LV septal wall thickness ≥15 mm) was confirmed in 21 of 41 patients. The septal hypertrophy group had higher peak aortic valve velocity, a higher diabetes mellitus rate, and a higher rate and longer duration of hypertension than those without septal hypertrophy. The peak aortic valve velocity (odds ratio, 7.1; 95% confidence interval, 1.4–37.1) and diabetes mellitus (odds ratio, 7.4; 95% confidence interval, 1.2–46.2) were the significant factors associated with septal hypertrophy by multivariate analysis. Intraventricular conduction disturbance on electrocardiography was more frequent in the septal hypertrophy group (P = .021).ConclusionsLeft ventricular septal hypertrophy was commonly observed in elderly patients with aortic stenosis, and a higher aortic valve velocity, hypertension, and diabetes mellitus were associated factors. Intraventricular conduction disturbance occurred more often in patients with septal hypertrophy than those without, which implies the pathophysiologic consequence. Further studies are needed to determine the impact of septal hypertrophy and intraventricular conduction disturbance on the prognosis of patients after aortic valve interventions.

AbstractRenal agenesis is a devastating birth defect, and although genes encoding retinoic acid signaling components have been shown to be important for renal...Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1. However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L. Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

AbstractBackgroundThe CYP11A1 gene encodes the cytochrome P450 side‐chain cleavage enzyme, which is essential for steroid formation. Recessive variants in this gene can lead to impairment of sexual differentiation caused by a complete or partial loss of steroid hormone production. The phenotypic spectrum in affected 46XY males may vary from surgically repairable defects including cryptorchidism and hypospadias to complete feminization of external gonads, accompanied by symptoms of adrenal dysfunction.MethodsWhole‐exome sequencing (WES) of a 12‐year‐old male proband and his parents was performed after a protracted diagnostic odyssey failed to uncover the cause of his primary adrenal insufficiency. Of note, the proband had early symptomatology and corrective surgery for hypospadias, raising suspicion for a disorder of steroidogenesis.ResultsWES identified compound heterozygous variants in CYP11A1 including a novel canonical splice site variant (c.425+1G>A) and a previously reported p.E314K variant, which were consistent with a diagnosis of congenital adrenal insufficiency with partial 46XY sex reversal.ConclusionCongenital adrenal insufficiency with 46XY sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G>A variant in trans with the p.E314K variant in CYP11A1. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site.

IN BRIEF Diabetes has been associated with the incidence of back pain. However, the relationship between markers of diabetes progression and back pain has not been studied. The objective of this study was to correlate clinical and laboratory measures of diabetes disease severity to the presence of back pain to provide insight into the relationship between these conditions. Findings showed that markers of diabetes disease progression were associated with the presence of back pain, suggesting that uncontrolled diabetes may contribute to the development of chronic back pain.