Budget impact analysis of rituximab biosimilar in Italy from the hospital and payer perspectives

Introduction: This article aims at investigating the 5-year budget impact of rituximab biosimilars in Italy. Methods: A budget impact analysis model was developed in accordance with the International Society For Pharmacoeconomics and Outcomes Research recommendations. Drug acquisition and drug administration costs were considered since the risk/benefit profile of biosimilars and the originator was assumed to be overlapping. The perspectives of hospitals and payers were used. Input data were retrieved from the literature and validated/integrated by an expert panel of seven clinicians from various Italian regions. A dynamic incidence-based approach was used. Results: From the hospital perspective, adopting a rituximab biosimilar would produce savings of €79.2 and €153.6 million over 3 and 5 years, respectively. The results are very similar if the payer perspective is considered, with a cumulated savings of about €153.4 million in 5 years. Lymphoma and chronic lymphocytic leukaemia would account for the most significant savings. Discussion: Despite its limitations, this study provides the first Italian evaluation of the financial impact of rituximab biosimilars and also incorporates the effects of biosimilars on the pricing strategies of the originator (dynamic impact). This dynamic effect is more relevant than the impact of the treatment shift from the originator to biosimilars. Our hope is that these savings will be used to cover new cost-effective drugs and not just for cost-cutting policies

A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL)1–3, but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function

Molecular origin of childhood acute lymphoblastic leukemia

Our understanding of the genetic etiology of pediatric acute lymphoblastic leukemia (ALL) has advanced greatly in the past few decades. Due to the advent of genome-wide profiling techniques for copy number alterations (CNAs) as well as sequence mutations, we have thoroughly characterized many different genetic subtypes of ALL. Each subtype harbors alterations activating leukemogenic pathways and differs in prevalence, prognosis, cell type, and treatment response. The interplay of founding leukemogenic aberrations, acquired mutations, and germline composition of the patient is important for the development and progression of the disease. Moreover, genomic profiling has identified genetic alterations that have been integrated into diagnostic testing algorithms and are being evaluated as targets for therapy. Despite these advances, the genetic basis of a minority of ALL cases remains unknown, and the frequency of these enigmatic cases rises with patient age. Much work remains in studying these last uncharacterized groups to fully understand leukemia development and improve outcomes

Melt inclusions from the deep Slave lithosphere : implications for the origin and evolution of mantle-derived carbonatite and kimberlite

Melt inclusions in clinopyroxenes from lherzolitic xenoliths from the deep lithospheric mantle beneath the Slave Craton (Lac de Gras area, Canada) reveal multiple origins for carbonatitic melts. One type of inclusions consists of a series of silicate–carbonate–silicate concentric layers, interpreted to have unmixed under disequilibrium conditions during rapid ascent to the surface. Bulk major- and trace-element compositions are typical of Group 1 kimberlites and quantitative nuclear microprobe imaging of the globules reveals fractionation of related elements (e.g. F–Br, Nb–Ta) between the silicate and carbonate components. The globules probably formed by partial melting of carbonated peridotite, consistent with results of melting experiments and some models for the generation of kimberlite magmas. They provide evidence for a genetic relationship between some carbonate-rich magmas and ultramafic silicate magmas, and for the possibility of unmixing processes of these melts during their evolution. The second inclusion type comprises carbonate-rich globules interpreted as samples of Mg-carbonatite melt that quenched on ascent to the surface. Bulk major- and trace-element compositions indicate that the melts were derived from a carbonate-rich source and oxygen, carbon, and strontium isotope data are consistent with the involvement of recycled crustal material and suggest that some mantle-derived carbonatites are unrelated to kimberlites.14 page(s

Subduction signature for quenched carbonatites from the deep lithosphere

Quenched carbonate-silicate inclusions in lherzolitic clinopyroxene macrocrysts, derived from 200 km beneath the Slave craton in northern Canada, are interpreted as natural samples of mantle carbonatites. Oxygen, carbon, and strontium isotope data provide evidence for the involvement of subducted crustal material in the origin of these carbonatites, supporting suggestions that carbon recycling by subduction is an important prerequisite for carbonatite magmatism. The compositional range of the inclusions suggests that the parent melt was decreasing in silica content as it was trapped in the host crystal, a trend that is predicted experimentally. Isotopic disequilibrium between the carbonatitic inclusions and the host clinopyroxene indicates that they were trapped shortly before kimberlite eruption, suggesting a temporal link between the entrapment of the carbonatite in the host and the Paleocene eruption of the kimberlite.4 page(s

Differential expression of the EGF-TM7 family members CD97 and EMR2 in lipid-laden macrophages in atherosclerosis, multiple sclerosis and Gaucher disease

The members of the epidermal growth factor (EGF)-transmembrane (TM)7 family of adhesion class G-protein coupled receptors are abundantly expressed by cells of the myeloid lineage. A detailed investigation of their expression by functional subsets of activated macrophages is still lacking. Therefore, we determined the expression of CD97, EGF module-containing mucin-like receptor (EMR)2 and EMR3 by monocyte-derived macrophages experimentally polarized in vitro. This was compared to three types of disease-associated lipid-laden macrophages displaying an alternatively activated phenotype in situ. Polarization in vitro towards classically activated M1 versus alternatively activated M2 extremes of macrophage activation did not result in a congruent regulation of EGF-TM7 receptor mRNA and protein except for a down-regulation of CD97 by IL-10. In contrast, macrophages handling lipid overload in vivo displayed differences in the expression of CD97 and EMR2. While foamy macrophages in atherosclerotic vessels expressed both CD97 and EMR2, foam cells in multiple sclerosis brain expressed CD97, but only little EMR2. Foam cell formation in vitro by oxidized LDL and myelin did not affect CD97 or EMR2 expression. Gaucher spleen cells accumulating glucosylceramide expressed very high levels of CD97 and EMR2. These findings indicate that complex cellular expression programmes rather than activation modes regulate the expression of EGF-TM7 receptors in macrophages. (C) 2010 Elsevier B.V. All rights reserve