Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression.

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Unstimulated leukapheresis in patients and donors: comparison of two apheresis systems.

BACKGROUND: Unstimulated mononuclear cell (MNC) apheresis plays a role in the generation of donor lymphocytes (DLIs; healthy donors) and in extracorporeal photopheresis (ECP; patients). The new apheresis system Spectra Optia MNC has been shown in small studies to be capable of performing the desired cell collections, but larger data sets from real-life clinical apheresis procedures are lacking. STUDY DESIGN AND METHODS: Presented are comparative data from DLI collections randomly performed with either the new technology or a clinical standard technology, COBE Spectra MNC, as well as data from patients with chronic graft-versus-host disease undergoing MNC collections alternating between the two apheresis systems to generate products for ECP. Target cell yield and collection efficiency, product volume, nontarget cell contamination, platelet (PLT) attrition, and some process variables such as process volume and time were analyzed. RESULTS: For most relevant apheresis outcomes, differences between the devices were at best marginal. Spectra Optia MNC collections in patients, but not in donors, took 10% longer to achieve the target process volume. Not unexpectedly, given previous observations for granulocyte-colony-stimulating factor-stimulated leukapheresis, the novel device collected smaller products with less red blood cell contamination. PLT attrition with Spectra Optia MNC was markedly lower in donors. ECP apheresis outcome variability was, to a significant degree, donor dependent, irrespective of the device used. CONCLUSION: Based on more than 200 unstimulated apheresis procedures, we conclude that both apheresis systems are safe, robust, and equally suitable for unstimulated MNC collections. Both can be successfully run with manufacturer-recommended settings and algorithms.

The societal impact of obinutuzumab in the first-line treatment of patients with follicular lymphoma in Germany.

In this study, we assessed the productivity gains associated with the use of obinutuzumab in combination with chemoimmunotherapy (G-chemo) in first-line treatment among follicular lymphoma patients. Health benefits, measured as an increase in progression-free survival, were translated into productivity gains in both paid and unpaid work using gross value added as productivity measure. From 2017 to 2030, 11,870 overall progression-free years can be gained by utilizing obinutuzumab. These progression-free years correspond to undiscounted productivity gains of about €187.9 million in paid work and about €535.9 million in unpaid work. Our study shows that the benefits of the use of obinutuzumab in the first-line treatment of follicular lymphoma extend beyond clinical advantages.

Chicken orthologues of mammalian imprinted genes are clustered on macrochromosomes and replicate asynchronously.

In the chicken genome, most orthologues of mouse imprinted genes are clustered on macrochromosomes. Only a few orthologues are located in the microchromosome complement. Macrochromosomal and, to a lesser extent, microchromosomal regions containing imprinted gene orthologues exhibit asynchronous DNA replication. We conclude that highly conserved arrays of imprinted gene orthologues were selected during vertebrate evolution, long before these genes were recruited for parent-specific gene expression by genomic imprinting mechanisms. Evidently, the macrochromosome complement provides a better chromatin environment for the establishment of asynchronous DNA replication and imprinted gene expression later in evolution than microchromosomes.

Expression profiling of uniparental mouse embryos is inefficient in identifying novel imprinted genes.

Imprinted genes are expressed from only one allele in a parent-of-origin-specific manner. We here describe a systematic approach to identify novel imprinted genes using quantification of allele-specific expression by Pyrosequencing, a highly accurate method to detect allele-specific expression differences. Sixty-eight candidate imprinted transcripts mapping to known imprinted chromosomal regions were selected from a recent expression profiling study of uniparental mouse embryos and analyzed. Three novel imprinted transcripts encoding putative non-protein-coding RNAs were identified on the basis of parent-of-origin-specific monoallelic expression in E11.5 (C57BL/6 x Cast/Ei)F1 and informative (C57BL/6 x Cast/Ei) x C57BL/6 backcross embryos. In addition, four transcripts with preferential expression of a strain-specific allele were found. Intriguingly, a vast majority of the analyzed transcripts showed no imprinting-associated expression in F1 embryos. These data strengthen the view that a large fraction of nonimprinted genes is differentially expressed between parthenogenetic and androgenetic embryos and question the efficiency of expression profiling of uniparental embryos to identify novel imprinted genes.