Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A

Berg, H. M. Van Den; Fischer, Kathelijn; Carção, Manuel; Chambost, Hérvè; Kenet, Gili; Kurnik, Karin; Königs, Chris; Male, Christoph; Santagostino, Elena; Ljung, Rolf

doi:10.1182/blood.2019000658

Cited by 77 publications

(62 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A subgroup especially relevant to post-marketing surveillance are PUPs, as with the end of mandatory clinical trials in PUPs with hemophilia, post-marketing data captured in hemophilia registries will become increasingly important to optimize hemophilia treatment for PUPs as compared to PTPs. One major difference between PUPs and PTPs is inhibitor risk, which is highest in PUPs just beginning treatment and much lower in PTPs [ 58 , 59 , 60 , 61 , 62 , 63 ]. To ensure relevance and completeness of patient data captured in this early stage of treatment, the dhr was harmonized with the designated PUP registries PedNet and GEPHARD.…”

Section: Resultsmentioning

confidence: 99%

The German Hemophilia Registry: Growing with Its Tasks

Duda

Hesse

Haschberger

et al. 2020

JCM

View full text Add to dashboard Cite

Hemophilia is a rare heredity bleeding disorder that requires treatment for life. While few therapeutic options were available in the past, multiple recent breakthroughs have fundamentally altered and diversified hemophilia therapy, with even more new therapeutic options forthcoming. These changes are mirrored by significant regulatory and legal changes, which have redefined the role of hemophilia registries in the European Union (EU). This dual paradigm shift poses new regulatory, scientific but also structural requirements for hemophilia registries. The aim of this manuscript is to enumerate these significant challenges and to demonstrate their incorporation into the redesign of the German Hemophilia Registry (Deutsches Hämophilieregister, dhr). To identify the spectrum of hemophilia therapies and the degree of regulatory changes, a horizon screening was performed. Consequently, a core dataset for the dhr was defined by harmonization with regulatory guidelines as well as other hemophilia registries and by heeding the needs of different stakeholders (patients, clinicians, regulators, and scientists). Based on this information, a new registry structure was established, which is optimized for capturing data on new and established hemophilia therapies in a changing therapeutic and regulatory landscape

show abstract

Section: Resultsmentioning

confidence: 99%

The German Hemophilia Registry: Growing with Its Tasks

Duda

Hesse

Haschberger

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…Among patients who do develop inhibitors, ∼70% of those who then receive ITI therapy achieve peripheral immune tolerance to FVIII, which is defined operationally as an inhibitor titer below 0.6 Bethesda units/mL (18,19). Many inhibitors develop within the first 20 FVIII infusions, following a classic prime + boost pattern (20), while inhibitor development after 50 FVIII exposure days is rare (21,22). Inhibitor development requires uptake, processing and MHC Class II presentation of FVIII peptides and subsequent recognition of the peptide-MHC Class II complexes by circulating T cells (23,24).…”

Section: Discussionmentioning

confidence: 99%

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

et al. 2020

View full text Add to dashboard Cite

Formation of pathological anti-FVIII antibodies, or "inhibitors," is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are not well-understood. To address these questions, temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) was carried out for HA subjects with and without a current or historic inhibitor using RNA-Seq. PBMCs were isolated from 40 subjects in the following groups: HA with an inhibitor that resolved either following ITI or spontaneously; HA with a current inhibitor; HA with no inhibitor history and non-HA controls. PBMCs were stimulated with 5 nM FVIII and RNA was isolated 4, 16, 24, and 48 h following stimulation. Time-series differential expression analysis was performed and distinct transcriptional signatures were identified for each group, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. Subjects with a current inhibitor showed differential expression of 56 genes and a clustering analysis identified three major temporal profiles. Interestingly, gene ontology enrichments featured innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A, and COLEC12. NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1β and TNFα, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. RNA-Seq results were validated by RT-qPCR, ELISAs, multiplex cytokine analysis, and flow cytometry. The inflammatory status of HA patients suffering from an ongoing inhibitor includes up-regulated innate immune modulators, which may act as ongoing danger signals that influence the responses to, and eventual outcomes of, ITI therapy.

show abstract

“…In the PedNet registry, patients were followed for up to 1000 exposure days. Recently published data showed that 79% of all inhibitors developed within 20 exposure days and 18% between 20 and 50 exposure days 16 …”

Section: Discussionmentioning

confidence: 99%

“…As of January 2018, the PedNet Haemophilia Registry had included 1035 patients with severe haemophilia A (factor VIII activity at baseline percentage ≤1%) from 31 haemophilia centres (http://www.pednet.eu, http://www.clinicaltrials.gov trial no: NCT02979119) 16,17 . To provide a contemporaneous comparison to the clinical study, we selected all PUPs treated with human recombinant FVIII octocog alfa who were born between 2000 and 2009.…”

Section: Methodsmentioning

confidence: 99%