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. 2021 Sep;19(9):2171-2181.
doi: 10.1111/jth.15419. Epub 2021 Jul 19.

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study

Amal Abdi  1 , Corien L Eckhardt  1 , Alice S van Velzen  1 , Caroline Vuong  1 , Michiel Coppens  2 , Giancarlo Castaman  3 , Dan P Hart  4 , Cedric Hermans  5 , Britta Laros-van Gorkom  6 , Frank W G Leebeek  7 , Maria Elisa Mancuso  8   9 , Maria G Mazzucconi  10 , Simon McRae  11 , Johannes Oldenburg  12 , Christoph Male  13 , Johanna G van der Bom  14   15 , Karin Fijnvandraat  1   16 , Samantha C Gouw  1   14 ; INSIGHT Study Group
Affiliations

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study

Amal Abdi et al. J Thromb Haemost. 2021 Sep.

Abstract

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs).

Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development.

Patients/methods: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression.

Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases.

Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

Keywords: anti-drug antibody; factor VIII; hemophilia A; inhibitor; risk factors.

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Conflict of interest statement

AA, CLE, ASV, CV, MGM, SM, and JGB have nothing to disclose. MC has received research grants from Bayer, CSL Behring, Daiichi Sankyo, Portola/Alexion, Roche, Sanquin Blood Supply, and UniQure, and consultancy and/or lecturing fees from Bayer, CSL Behring, Medcon International, MED talks, NovoNordisk, Pfizer, and Sobi. GC has received speaker, consultancy, and/or advisory fees from Ablynx, Bayer, CSL Behring, Kedrion, Novo Nordisk, Shire/Takeda, Sobi, Roche, UniQure, and Werfen, and research grants from CSL Behring, Pfizer, and Sobi. DPH has received research grants from Bayer, Octapharma, and Takeda, and advisory and/or lecturing fees from Bayer, Biomarin, Biotest, Grifols, Octapharma, Pfizer, Roche, Sanofi, Sobi, Takeda, and UniQure. CH has received consultancy and/or lecturing fees from Pfizer, Bayer, Shire/Takeda, Sobi, Biogen, CAF‐DCF, CSL Behring, LFB, Novo Nordisk, Roche, Octapharma, and Kedrion, and research funding from Pfizer, Bayer, Shire/Takeda, and Sobi. BL has received research grants from Baxter and CSL Behring. FWGL has received research support from CSL Behring, Shire/Takeda, UniQure, and Sobi and consultancy fees from UniQure, Novo Nordisk, Biomarin, and Shire/Takeda. He is a DSMB member for a study by Roche. MEM has received consultancy, advisory, and/or speaker fees from Bayer, CSL Behring, Catalyst, Biomarin, Kedrion, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Takeda. JO has received honoraria and consulting fees from Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Shire, and grants from CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Shire. CM has received personal honoraria, travel support, fees to institution for study patients, and/or unrestricted grants from Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Grifols, Novo Nordisk, Roche, and SOBI. KF has received unrestricted research grants from CSL Behring, Novo Nordisk, and consultancy fees from Grifols, Takeda, and Novo Nordisk. SCG has received an unrestricted research grant from Sobi.

Figures

FIGURE 1
FIGURE 1
Flowchart of patient inclusion. ED, exposure day; Early inhibitor patients: ≤50 EDs prior to inhibitor development; Late inhibitor patients >50 EDs prior to inhibitor development. From the INSIGHT cohort (N = 2709), 104 inhibitor patients and 333 matched controls were selected. Of these patients, 15 inhibitor patients and 67 controls were excluded because only baseline data were available (no data on exposure days). In this study, 355 patients were included on whom detailed data on the last 10 cumulative EDs were available. *In the early inhibitor group (n = 63), 36 (57%) patients had a high‐titer inhibitor. In the late inhibitor group (n = 26), 13 (50%) patients had a high‐titer inhibitor
FIGURE 2
FIGURE 2
Distribution of F8 genotypes. The four graphs illustrate the distribution of F8 genotypes on the A1‐3, C1‐2, and B domains of the FVIII protein in cases and controls. Abbreviations: UK, unknown
See this image and copyright information in PMC

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