Impact of screening and exclusion of high anti‐A titer donors on the risk of hemolytic anemia with intravenous immunoglobulin treatment: A hospital‐based cohort study in the US

Martínez, Carlos; Watson, Douglas J.; Shebl, Amgad; Wallenhorst, Christopher; Hubsch, Alphonse; Simon, Toby L.

doi:10.1002/ajh.24931

Cited by 7 publications

(9 citation statements)

References 4 publications

(6 reference statements)

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“…). This indicates that IVIG‐related hemolysis is primarily a high‐dose adverse reaction as shown in previous scientific literature …”

Section: Resultssupporting

confidence: 79%

“…CSL Behring implemented a donor screening and exclusion program for IgPro10 from 2014 to 2016. Exclusion of approximately 5% of donors with high anti‐A titers resulted in a modest reduction of isoagglutinin titers in the final IVIG product, which was followed by a reduction of hemolytic events as seen here and in an observation study . Both isoagglutinin content and hemolysis data shown here suggest that donor screening is less effective than IAC .…”

Section: Discussionmentioning

confidence: 49%

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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

et al. 2020

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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.

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“…). This indicates that IVIG‐related hemolysis is primarily a high‐dose adverse reaction as shown in previous scientific literature …”

Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 49%

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

et al. 2020

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“…A stand‐alone donor screening program, excluding donors with the highest anti‐A titers (approx. 5% of the donor pool), is predicted to produce a modest reduction of HE risk compared with the risk from a product without any isoagglutinin reduction, consistent with the reduction demonstrated in an observational cohort study . This reduction of risk is expected not only in patients with blood groups A and AB, but also in those with blood group B, consistent with the correlation of anti‐B with anti‐A in blood donors .…”

Section: Discussionsupporting

confidence: 73%

Hemolytic adverse effects of intravenous immunoglobulin: modeling predicts risk reduction with anti‐A/B immunoaffinity chromatography and to a lesser extent with anti‐A donor screening

Mallick

Hubsch

Barnes³

2018

Transfusion

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BACKGROUND: The risk of hemolytic events (HEs) with intravenous immunoglobulin (IVIG) therapy appears to be linked to isoagglutinins (anti-A and anti-B) in the product. Patient risk factors include high IVIG dose, blood group, and underlying inflammatory state. STUDY DESIGN AND METHODS: Using publishedanti-A and anti-B titers for IVIG products and HE rates calculated from HEs spontaneously reported to EudraVigilance, regression models were developed to infer the relationship between HE risk and IVIG isoagglutinin levels for each blood group. Applying estimated model coefficients to isoagglutinin levels associated with an IVIG (Privigen; CSL Behring, King of Prussia, PA), manufactured with and without isoagglutinin reduction steps, predicted HE risk values were generated for each product: 1) without any isoagglutinin reduction, 2) anti-A donor screening, and 3) anti-A/anti-B specific immunoaffinity chromatography (IAC; Ig IsoLo). RESULTS:Predicted HE risk was highest for blood group AB, followed by A and B; it was low for O. Projected population shares of HEs by blood group were similar to reported real-world data. Compared with the original process (no isoagglutinin reduction), the model predicts lower hemolytic risk with anti-A donor screening and even lower hemolytic risk with IAC isoagglutinin reduction. CONCLUSION: IAC isoagglutinin reduction is predictedto reduce the HE risk with IVIG substantially. Physicians should be especially vigilant to HE risk in patients with blood group AB and, to a lesser extent, A when using IVIG products with high anti-A titers.

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“…Hemolytic events were observed in both trials. The trials were undertaken before the implementation of an immunoaffinity chromatography step in the production process, which lowers isoagglutinin levels by 75% to 88%, and is expected to reduce the incidence of hemolytic events seen in future studies . The safety results from the combined analysis support that IgPro10 is a well‐tolerated treatment option when administered as induction and maintenance infusions to subjects with CIDP.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies

Merkies

Schaik

Léger

et al. 2019

J Peripheral Nervous Sys

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Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open‐label, single‐arm study of IVIG in immunoglobulin (Ig)‐naïve or IVIG pre‐treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double‐blind, randomized study including an open‐label, single‐arm IVIG phase in IVIG pre‐treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre‐treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was −1.0 (interquartile range −2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score . In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA‐approved IVIG for CIDP, in a population of mainly pre‐treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].

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Impact of screening and exclusion of high anti‐A titer donors on the risk of hemolytic anemia with intravenous immunoglobulin treatment: A hospital‐based cohort study in the US

Cited by 7 publications

References 4 publications

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

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

Hemolytic adverse effects of intravenous immunoglobulin: modeling predicts risk reduction with anti‐A/B immunoaffinity chromatography and to a lesser extent with anti‐A donor screening

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies

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