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.

Safety and tolerability of IgPro10 in Japanese primary immunodeficiency patients: a registrational study.

Studies investigating the safety of IgPro10 (Privigen®, CSL Behring, King of Prussia, PA, USA) in Japanese patients with primary immunodeficiency (PID) are lacking. This study evaluated safety and tolerability of IgPro10 in Japanese patients with PID. In this prospective, open-label, single-arm, registrational study for Japan, IgPro10 was administered intravenously at pre-study doses of 138-556 mg/kg body weight per 3-/4-weekly dosing cycle for up to 4 months. Frequency and intensity of adverse events (AEs), their relationship to IgPro10 and AE rate per infusion (AERI) were evaluated. Of 11 enrolled patients, 10 completed the study. The median (range) total duration of exposure was 16.14 (4.1-16.3) weeks. Eight patients reported 19 AEs, none severe (based on maximum severity), giving an AERI of 0.442. One AE was deemed related to IgPro10 treatment. Three patients experienced temporally associated AEs. No serious AEs or deaths were reported. Nine patients (90%) who completed the study tolerated flow rates of ≥ 8 mg/kg/min; 5 tolerated 12 mg/kg/min (7.2 mL/kg/h), translating into a threefold decrease in mean infusion time. IgPro10 was well tolerated at a flow rate of up to 12 mg/kg/min. Safety and tolerability findings were consistent with previously reported studies in non-Japanese patients with PID.

Anti-A/B isoagglutinin reduction in an intravenous immunoglobulin product and risk of hemolytic anemia: a hospital-based cohort study.

BACKGROUND: Intravenous immunoglobulins (IVIG) are derived from large human plasma pools. IVIG-associated hemolytic anemia (HA) is a known class effect, likely attributed to dose-dependent passive transfer of anti-A/B isoagglutinins. Two isoagglutinin reduction steps were implemented in the manufacturing process of Privigen (human 10% liquid IVIG): exclusion of high-anti-A-titer donors in 2013, replaced by specific immunoaffinity chromatography in 2015. We aim to estimate the clinical effectiveness of both measures. STUDY DESIGN AND METHODS: Using the US hospital-based Premier Healthcare Database, three Privigen cohorts were generated based on calendar periods indicative of manufacturing changes: Period 1 (baseline) January 2008 to December 2012, Period 2 (high-anti-A-titer donor exclusion) October 2013 to December 2015, and Period 3 (immunoaffinity chromatography) October 2016 to April 2019. HA within a 10-day at-risk period after Privigen administrations was identified from review of patient record summaries. Incidence rate ratios (IRRs) were estimated from Poisson regression (Period 1 reference) adjusting for hospital setting, sex, age, Privigen indication, dose, and first use. RESULTS: Crude incidence rates of HA were 1.49 per 10,000 person-days in Period 1 (38 HA, 9439 patients), 1.01 in Period 2 (20 HA, 7710 patients), and 0.14 in Period 3 (3 HA, 7759 patients). Adjusted IRR for HA in Period 2 was 0.71 (95% confidence interval [CI], 0.41-1.23), and in Period 3 was 0.10 (0.03-0.33) compared with Period 1. The IRR for HA in Period 3 compared with Period 2 was 0.14 (95% CI, 0.04-0.47). CONCLUSION: Implementation of immunoaffinity chromatography in Privigen manufacturing resulted in a significant 90% reduction of HA risk. HA has become a rare event in association with Privigen use.

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.

Measurement of isoagglutinins in immunoglobulins for intravenous application by flow cytometry.

Isoagglutinins present in intravenous immunoglobulin (IVIG) products have been linked to haemolysis. Therefore, accurately assessing isoagglutinin content in IVIG products is important. The standard European Pharmacopoeia (Ph.Eur.) direct assay is limited by low precision. Here, we describe the development of a fluorescence-activated cell sorting (FACS) method for assessing isoagglutinin levels. Serially diluted IVIG samples were incubated with red blood cells (RBCs), RBC-bound anti-A and anti-B antibodies were detected using a fluorescently-labelled antibody and the median fluorescence intensity of samples was assessed by FACS. Results were compared with the Ph.Eur. direct assay. The method was used to determine isoagglutinins in commercial products produced with and without isoagglutinin reduction steps. Assay precision, reported as the coefficient of variation, for the FACS method was 14% and 8% for anti-A and anti-B, respectively versus 33% and 20% with the Ph.Eur. direct assay. Application of the method on commercially available IVIGs revealed differences in isoagglutinin content between products produced with and without isoagglutinin reduction steps. This FACS assay allows for quantification of isoagglutinin concentrations in IVIGs with higher precision than the Ph.Eur. direct assay. Also the FACS assay confirms differences in isoagglutinin levels between IVIG products and the efficacy of isoagglutinin reduction measures.

Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study.

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal.

Hemolysis related to intravenous immunoglobulins is dependent on the presence of anti-blood group A and B antibodies and individual susceptibility.

BACKGROUND: Patients treated with intravenous immunoglobulins (IVIG) rarely experience symptomatic hemolysis. Although anti-A and anti-B isoagglutinins from the product are involved in most cases, the actual mechanisms triggering hemolysis are unclear. STUDY DESIGN AND METHODS: A prospective, open-label, multicenter, single-arm clinical trial in 57 patients with immune thrombocytopenia treated with IVIG (Privigen, CSL Behring) was conducted. RESULTS: Twenty-one patients received one infusion (1 g/kg) and 36 received two infusions (2 × 1 g/kg) of IVIG. After a study duration of more than 2 years, no cases of clinically significant hemolysis as defined in the protocol were identified. Data of patients with mild hematologic and biochemical changes were analyzed in more detail. Twelve cases (10/23 patients with blood group A1 and 2/11 patients with blood group B, all having received 2 g/kg IVIG) were adjudicated as mild hemolysis (median hemoglobin [Hb] decrease, -3.0 g/dL); Hb decreases were transient, with partial or full recovery achieved by last visit. Eighteen patients (31.6%), all with non-O blood group, of whom 16 (88.9%) received 2 g/kg IVIG, fulfilled post hoc criteria for hemolytic laboratory reactions. Red blood cell (RBC) eluates of all direct antiglobulin test-positive samples were negative for non-ABO blood group antibodies. Blood groups A and B antigen density on RBCs appeared to be a risk factor for hemolytic laboratory reactions. Platelet response to treatment was observed in 42 patients (74%); eight of 12 patients with complete response had blood group A1. CONCLUSION: Isoagglutinins are involved in clinically nonsignificant hemolysis after treatment with IVIG, but individual susceptibility varies greatly.

Hemolytic events associated with intravenous immune globulin therapy: a qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012.

BACKGROUND: Objectives of this study were to identify possible patient and product risk factors for intravenous immune globulin (IVIG)-associated hemolysis, a recognized side effect of IG therapy; analyze IVIG indications; and examine dose levels (g/kg body weight) and total IVIG dose administered. STUDY DESIGN AND METHODS: Reports of IVIG-associated hemolysis for 10 years (2003-2012) for four participating IG manufacturers were identified using a uniform case definition (Standardized MedDRA Query "Hemolytic disorders," Broad Scope, Version 16.0) and analyzed. RESULTS: IVIG-associated hemolysis appears to occur predominantly at dose levels exceeding 0.5 g/kg, with 72% of cases with known dose information having dose levels between 1 and 2.5, and can affect patients at any age, without a clear gender preference. No association was found between hemagglutinin exposure and development of hemolysis, nor between dose levels and odds of receiving a transfusion to treat hemolysis. Patients with blood group AB may be at higher risk of hemolysis than those with group A or B. CONCLUSION: Data examined confirm that IVIG-associated hemolysis predominantly occurs following infusion of high IVIG doses, and can affect patients at every age of both genders. While presence of hemagglutinins appears to play a major role in pathogenesis of hemolytic disorders, high hemagglutinin titers of IVIG products themselves seem to be of less relevance, indicating that the pathomechanism of IVIG-associated hemolysis may be related to the presence, but not the absolute amount, of hemagglutinins. Patients with hemolysis had additional hemolytic risks such as multiple comorbidities and medication use. IG-treated patients with multiple risks should be closely monitored for hemolysis.

Efficacy and safety of Privigen(®) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study).

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen(®) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with L-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naïve patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP.