Incidence and risk factors for intravenous immunoglobulin-related hemolysis: A systematic review of clinical trial and real-world populations.

BACKGROUND: Severe hemolysis rarely occurs in patients receiving intravenous immunoglobulin (IVIG) therapy. A systematic review was performed to assess the incidence of IVIG-related hemolysis and the impact of patient and product risk factors. STUDY DESIGN AND METHODS: A systematic literature search for terms related to "IVIG products", "hemolysis," and "adverse events" was conducted in Embase for articles published between January 1, 2015, and May 31, 2021. Studies with no clinical datasets, no IVIG treatment, or where IVIG was used to treat hemolytic conditions were excluded. Of the 430 articles retrieved, 383 were excluded based on titles/abstracts and 14 were excluded after in-depth review. RESULTS: In total, 33 articles were analyzed and separated into observational studies (n = 16), clinical trials (n = 8), and case reports (n = 9). The incidence proportion for IVIG-related hemolysis ranged from 0% to 19% in observational studies and 0%-21% in clinical trials. A higher incidence of IVIG-related hemolysis was consistently reported in patients with blood groups A and AB. Hemolysis occurred more frequently in patients treated with IVIG for some conditions such as Kawasaki disease; however, this may be confounded by the high dose of IVIG therapy. IVIG-related hemolysis incidence was lower in studies using IVIG products citing manufacturing processes to reduce isoagglutinin levels than products that did not. CONCLUSION: This analysis identified patient and product risk factors including blood group, IVIG dose, and IVIG manufacturing processes associated with elevated IVIG-related hemolysis incidence.

Isoagglutinin reduction in intravenous immunoglobulin (IgPro10, Privigen) by specific immunoaffinity chromatography reduces its reporting rates of hemolytic reactions: an analysis of spontaneous adverse event reports.

BACKGROUND: Hemolysis is an infrequent but recognized and potentially serious adverse effect of intravenous immunoglobulin (IVIG). Relatively elevated hemolysis reporting rates were seen with some IVIG products with high anti-A/B isoagglutinin content, among which IgPro10 (Privigen, CSL Behring). For IgPro10, two isoagglutinin reduction measures were successively implemented: 1) anti-A donor screening and 2) immunoaffinity chromatography (IAC; Ig IsoLo)-based isoagglutinin reduction step included in the production process. The aim of this analysis was to investigate the effects of these isoagglutinin reduction measures on the reporting rates of IgPro10 hemolysis worldwide. STUDY DESIGN AND METHODS: Between February 2008 and December 2018, hemolysis reports from the CSL Behring Global Safety Database were analyzed in relationship to changes in IVIG IgPro10 production methods. Further analysis classified hemolysis reports by indication and blood group. RESULTS: Median (minimum-maximum) anti-A/anti-B titers were 32 (8-64)/16 (8-32) at baseline, 32 (8-64)/16 (8-32) after donor screening, and 8 (8-32)/4 (2-8) after implementation of IAC. The reporting rate of hemolytic reactions per 1000 kg IgPro10 sold was 4.05 cases at baseline, 2.00 after donor screening, and 0.50 after implementation of IAC. In 2018, there were seven reports of hemolytic reactions; representing 0.18 cases per 1000 kg IgPro10 sold, with a reduction of 95.6% versus baseline. CONCLUSION: Following implementation of the IAC isoagglutinin reduction step, spontaneous reports of hemolytic events with IgPro10 were significantly and consistently reduced versus IgPro10 without isoagglutinin reduction, offering patients a more favorable benefit-risk profile.

Effects of the manufacturing process on the anti-A isoagglutinin titers in intravenous immunoglobulin products.

BACKGROUND: The first intravenous immunoglobulin G (IVIG) preparations for clinical use were produced from human plasma by Cohn-like fractionation processes. To achieve higher purity and yield, chromatography-based processes were developed. Using two products as examples, we compare the capacity of these two manufacturing processes to reduce the levels of anti-A and anti-B isoagglutinins in IVIG, which are believed to be responsible for rare hemolytic adverse events. STUDY DESIGN AND METHODS: The isoagglutinin levels of Sandoglobulin (lyophilized, sucrose-stabilized IVIG produced by Cohn-like fractionation) and Privigen (10% l-proline-stabilized IVIG produced by a chromatography-based process) were measured by the indirect agglutination test (IAT). The intrinsic isoagglutinin reduction capacity of each fractionation step was assessed in laboratory- and industry-scale experiments using the IAT and a flow cytometry-based immunoglobulin-binding assay, respectively. RESULTS: The median anti-A isoagglutinin titer recorded in 248 Sandoglobulin lots was three titer steps lower than the one measured in 651 Privigen lots (1:2 vs. 1:16). Over the entire process, we measured a five-titer-step isoagglutinin reduction in laboratory-scale Cohn-like fractionation; the largest reduction was observed between Fraction (F)II+III and FII. An overall four-titer-step reduction was recorded in the industry-scale process. In contrast, none of the steps of the chromatography-based manufacturing process caused any decrease in anti-A isoagglutinin content. Similar results were obtained for anti-B isoagglutinin reduction. CONCLUSION: Unlike Cohn-like fractionation, chromatography-based IVIG manufacturing processes do not have an intrinsic capacity for isoagglutinin reduction. The addition of dedicated isoagglutinin reduction steps may help minimize the potential risk of hemolysis in IVIG-treated patients.

Isoagglutinin reduction by a dedicated immunoaffinity chromatography step in the manufacturing process of human immunoglobulin products.

BACKGROUND: The passive transfer of antibodies specific to blood groups A and B (also called isoagglutinins) contained in immunoglobulin (Ig)G products for intravenous administration (IVIG) is believed to be largely responsible for rare but sometimes serious IVIG-related hemolytic events. We present in this work a modification of the manufacturing process of Privigen-a 10% l-proline-stabilized IVIG product-that allows extensive reduction of isoagglutinin concentrations in the final product. STUDY DESIGN AND METHODS: An additional immunoaffinity chromatography (IAC) step was introduced toward the end of the manufacturing process of Privigen. Isoagglutinin titers were measured using the indirect agglutination method and a published flow cytometry-based binding assay. Quality attributes, such as microorganism counts and concentration of endotoxins, IgG, IgA, IgM, aggregates, and so forth were measured using standardized procedures. RESULTS: The introduction of an IAC step in the manufacturing process of Privigen resulted in an 88% to 90% reduction in isoagglutinins between the feed of the chromatography column and the flow-through fraction. All other product quality attributes measured were nearly identical before and after IAC. This process modification resulted in a three-titer-step reduction in isoagglutinin levels in the final IgG product compared to Privigen lots produced by the unmodified process. CONCLUSION: Introducing an isoagglutinin-specific IAC step in the manufacturing process of Privigen is an efficient strategy for reduction of anti-A and anti-B titers. Such reductions might help minimize the risk of hemolytic events in patients receiving IVIG therapy.