Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivoluma

Study on essential derivation in maize: III. Selection and evaluation of a panel of single nucleotide polymorphism loci for use in European and North American germplasm

Pairwise distance data for maize (Zea mays L.) inbred lines generated using sets of single nucleotide polymorphisms (SNPs) selected from a 50k Infinium array were compared with pairwise distances generated using a set of 163 simple sequence repeat (SSR) loci previously identified to help determine essentially derived variety (EDV) status (UPOV, 1991). Final comparisons were made using 26,874 SNPs after discarding SNPs with insufficient data quality or vulnerability to ascertainment bias. Inbred lines developed in the United States or in western Europe that had been previously published to establish SSR-based thresholds provided the means to determine equivalent SNP-based protocols. Use of 3072 SNPs selected to provide even genomic coverage according to genetic and physical maps provided robust, precise, high discrimination among inbred lines with consistent zonal classification with up to 20% missing data. Comparisons of intercepts and slopes for SSR and SNP inbred pairwise distance data translated the 82% SSR green-orange similarity threshold to 91% using SNPs and the 90% SSR orange-red threshold to 95% using SNPs. Information required to conduct analyses using these 3072 SNPS is presented

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study

Background Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.Methods We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort.Findings Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]).Interpretation The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. Copyright (C) 2019 Elsevier Ltd. All rights reserved

Immunologic non-inferiority of a newly licensed inactivated trivalent influenza vaccine versus an established vaccine: A randomized study in US adults

A trivalent inactivated influenza vaccine (Fluarix™, GlaxoSmithKline Biologicals) was licensed under US accelerated approval regulations. We performed a randomized, observer-blind, post-approval study to demonstrate its immunological non-inferiority versus an established US-licensed vaccine (primary endpoint). Adult (including elderly) subjects received a single injection of newly-licensed vaccine (n = 923) or established vaccine (n = 922). Serum hemagglutination-inhibition titers were determined pre-vaccination and 21–28 days after vaccination. Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI] ≤1.5) and difference in seroconversion rate (upper 95% CI ≤0.1) for all three vaccine strains. Safety was monitored for 6 months. The newly-licensed vaccine was non-inferior to the established vaccine in all subjects (≥18 years) and in elderly subjects (≥65 years). Adjusted GMT ratios (established/newly-licensed) against the H1N1, H3N2 and B strains were 0.65 (95% CI: 0.58, 0.73), 0.93 (0.83, 1.04) and 1.13 (1.03, 1.25) for all subjects and 0.75 (0.67, 0.85), 0.95 (0.82, 1.09) and 1.13 (1.00, 1.27) for elderly subjects. Corresponding values for the differences in seroconversion rate (established minus newly-licensed) were −0.12 (−0.16, −0.07), −0.02 (−0.06, 0.03) and 0.01 (−0.04, 0.06) for all subjects and −0.11 (−0.16, −0.05), −0.02 (−0.07, 0.04) and 0.02 (−0.04, 0.08) for elderly subjects. The most common adverse events with both vaccines were injection site pain, fatigue and headache, and no serious adverse events or deaths were considered related; there were no clinically relevant differences between the vaccines. In conclusion, the newly-licensed vaccine was well tolerated and immunologically non-inferior to the established vaccine for all three vaccine strains in the whole population and the elderly