Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)

Kathelijn Fischer; Riitta Lassila; Flora Peyvandi; Alexander Gatt; Samantha C. Gouw; Rob Hollingsworth; Thierry Lambert; Radek Kaczmarek; Diana Carbonero; Mike Makris

doi:10.1016/j.rpth.2024.102461

Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)

Kathelijn Fischer^*, Riitta Lassila, Flora Peyvandi, Alexander Gatt, Samantha C. Gouw, Rob Hollingsworth, Thierry Lambert, Radek Kaczmarek, Diana Carbonero, Mike Makris,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. Methods: Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. Results: For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01). For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. Conclusion: Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.

Original language	English
Article number	102461
Number of pages	7
Journal	Research and practice in thrombosis and haemostasis
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.rpth.2024.102461
Publication status	Published - May 2024

Keywords

antibodies
factor VIII
hemophilia A
hemophilia B
inhibitor
neutralizing factor
PTP
registries

Access to Document

10.1016/j.rpth.2024.102461Licence: CC BY-NC-ND

1-s2.0-S247503792400150X-mainFinal published version, 538 KBLicence: CC BY-NC-ND

Cite this

Fischer, K., Lassila, R., Peyvandi, F., Gatt, A., Gouw, S. C., Hollingsworth, R., Lambert, T., Kaczmarek, R., Carbonero, D., Makris, M. (2024). Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS). Research and practice in thrombosis and haemostasis, 8(4), Article 102461. https://doi.org/10.1016/j.rpth.2024.102461

@article{d9aa93c98f3845c99111385718aeb7fa,

title = "Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)",

abstract = "Background: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. Methods: Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. Results: For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01). For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. Conclusion: Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.",

keywords = "antibodies, factor VIII, hemophilia A, hemophilia B, inhibitor, neutralizing factor, PTP, registries",

author = "Kathelijn Fischer and Riitta Lassila and Flora Peyvandi and Alexander Gatt and Gouw, {Samantha C.} and Rob Hollingsworth and Thierry Lambert and Radek Kaczmarek and Diana Carbonero and Mike Makris and Cihan Ay and Christoph Male and Cedric Hermans and Peter Verhamme and Toshko Lissitchkov and Marios Antoniades and Miroslav Penka and Jan Blatny and Vladimir Komrska and Poulsen, {Lone Hvitfeldt} and Peter Kampmann and Lehtinen, {Anna Elina} and Sophie Susen and Yesim Dargaud and Christine Biron and Roseline D'Oiron and Annie Harroche and Robert Klamroth and Johannes Oldenburg and Martina Buehrlen and Wolfgang Miesbach and Florian Langer and Patrick Spannag and Martin Oliveri and Helen Platokouki and Efrosyni Nomikou and Olga Katsarou and Vasileia Garypidou and Marina Economou and Laszlo Nemes and Beatrice Nolan and Niamh O'Connell and Radossi Paolo and Giancarlo Castaman and Angiola Rocino and Ezio Zanon and Annarita Tagliaferri and Giancarlo Agnelli and Roger Schutgens and {Anzej Doma}, Sasa",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = may,

doi = "10.1016/j.rpth.2024.102461",

language = "English",

volume = "8",

number = "4",

}

Fischer, K, Lassila, R, Peyvandi, F, Gatt, A, Gouw, SC, Hollingsworth, R, Lambert, T, Kaczmarek, R, Carbonero, D, Makris, M 2024, 'Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)', Research and practice in thrombosis and haemostasis, vol. 8, no. 4, 102461. https://doi.org/10.1016/j.rpth.2024.102461

Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS). / Fischer, Kathelijn; Lassila, Riitta; Peyvandi, Flora et al.
In: Research and practice in thrombosis and haemostasis, Vol. 8, No. 4, 102461, 05.2024.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Inhibitor development according to concentrate after 50 exposure days in severe hemophilia

T2 - data from the European HAemophilia Safety Surveillance (EUHASS)

AU - Fischer, Kathelijn

AU - Lassila, Riitta

AU - Peyvandi, Flora

AU - Gatt, Alexander

AU - Gouw, Samantha C.

AU - Hollingsworth, Rob

AU - Lambert, Thierry

AU - Kaczmarek, Radek

AU - Carbonero, Diana

AU - Makris, Mike

AU - Ay, Cihan

AU - Male, Christoph

AU - Hermans, Cedric

AU - Verhamme, Peter

AU - Lissitchkov, Toshko

AU - Antoniades, Marios

AU - Penka, Miroslav

AU - Blatny, Jan

AU - Komrska, Vladimir

AU - Poulsen, Lone Hvitfeldt

AU - Kampmann, Peter

AU - Lehtinen, Anna Elina

AU - Susen, Sophie

AU - Dargaud, Yesim

AU - Biron, Christine

AU - D'Oiron, Roseline

AU - Harroche, Annie

AU - Klamroth, Robert

AU - Oldenburg, Johannes

AU - Buehrlen, Martina

AU - Miesbach, Wolfgang

AU - Langer, Florian

AU - Spannag, Patrick

AU - Oliveri, Martin

AU - Platokouki, Helen

AU - Nomikou, Efrosyni

AU - Katsarou, Olga

AU - Garypidou, Vasileia

AU - Economou, Marina

AU - Nemes, Laszlo

AU - Nolan, Beatrice

AU - O'Connell, Niamh

AU - Paolo, Radossi

AU - Castaman, Giancarlo

AU - Rocino, Angiola

AU - Zanon, Ezio

AU - Tagliaferri, Annarita

AU - Agnelli, Giancarlo

AU - Schutgens, Roger

AU - Anzej Doma, Sasa

PY - 2024/5

Y1 - 2024/5

N2 - Background: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. Methods: Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. Results: For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01). For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. Conclusion: Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.

AB - Background: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. Methods: Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. Results: For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01). For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. Conclusion: Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.

KW - antibodies

KW - factor VIII

KW - hemophilia A

KW - hemophilia B

KW - inhibitor

KW - neutralizing factor

KW - PTP

KW - registries

UR - http://www.scopus.com/inward/record.url?scp=85196774265&partnerID=8YFLogxK

U2 - 10.1016/j.rpth.2024.102461

DO - 10.1016/j.rpth.2024.102461

M3 - Article

AN - SCOPUS:85196774265

SN - 2475-0379

VL - 8

JO - Research and practice in thrombosis and haemostasis

JF - Research and practice in thrombosis and haemostasis

IS - 4

M1 - 102461

ER -

Inhibitor development according to concentrate after 50 exposure days in severe hemophilia: data from the European HAemophilia Safety Surveillance (EUHASS)

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this