Minor surgical procedures during immune tolerance induction in people with hemophilia A and inhibitors: results from the Brazilian Immune Tolerance (BrazIT) study cohort

Camelo, Ricardo Mesquita; Dias, Maíse Moreira; Rezende, Suely Meireles; ,

doi:10.1016/j.htct.2024.05.010

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Original article • Hematol., Transfus. Cell Ther. 46 (Suppl 2) • 2024 • https://doi.org/10.1016/j.htct.2024.05.010 linkcopy

Minor surgical procedures during immune tolerance induction in people with hemophilia A and inhibitors: results from the Brazilian Immune Tolerance (BrazIT) study cohort

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Introduction Surgeries are implicated in the development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) in hemophilia A individuals with immune tolerance induction (ITI) treatment being the recommended therapy to eradicate these inhibitors. We evaluated the association of surgical procedures performed during ITI and treatment outcome.

Methods Patients were treated according to the Brazilian ITI Protocol with outcomes being defined as successful (i.e., recovered responsiveness to exogenous FVIII) and failed (i.e., unresponsiveness to exogenous FVIII thus requiring bypassing agents for bleeding control). Surgical procedures during induction therapy were managed following international recommendations.

Results Treatment success rate was 68.7 % in 163 patients; 33 (20.2 %) were submitted to 43 (96 %) minor and two major surgeries. Personal, hemophilia, inhibitor, and treatment characteristics were similar between patients submitted to surgical procedures or not while on ITI; the success rates were 72.7 % and 67.7 % (p-value = 0.577), respectively.

Conclusion No association was found between having a minor surgical procedure and ITI treatment outcome.

Keywords
Hemophilia A; Inhibitors; Immune tolerance induction; Surgery; Outcome

Characteristic	Total (n = 163)	Missing data	Surgery (n = 33)	No surgery (n = 130)	p-value
Patient and hemophilia characteristics
Male n (%)	162 (99.4 %)	0	33 (100.0 %)	129 (99.2 %)	0.613†
White n (%)	88 (54.0 %)	0	22 (66.7 %)	66 (50.8 %)	0.102†
Age at diagnosis of hemophilia A - years, median (IQR)	0.9 (0.5-1.4)	6	0.8 (0.6-1.4)	0.9 (0.5-1.4)	0.687‡
Severe disease n (%)	145 (91.2 %)	4	30 (90.9 %)	115 (91.3 %)	0.948†
F8 genotype n (%)	142 (87.1 %)	21
High-risk mutation	129 (90.9 %)		30 (100.0 %)	99 (88.4 %)	0.050†
Inversion of intron 22	69 (48.6 %)
Inversion of intron 1	3 (2.1 %)
Frameshift	20 (14.1 %)
Nonsense	24 (16.9 %)
Large deletion	13 (9.2 %)
Low-risk mutation	13 (9.1 %)	0	0 (0.0 %)	13 (11.6 %)
Missense	7 (4.9 %)
Splice-site	6 (4.2 %)
Inhibitor characteristic
Age at inhibitor diagnosis - years median (IQR)	3.4 (1.6-9.3)	0	3.1 (1.6-7.1)	3.7 (1.6-10.1)	0.660‡
Interval between diagnoses of hemophilia A and inhibitor - years median (IQR)	2.0 (0.7-6.2)	6	1.6 (0.7-5.2)	2.1 (0.7-6.4)	0.666‡
High-response inhibitor n (%)	157 (96.3 %)	0	32 (97.0 %)	125 (96.2 %)	0.824†
Historic inhibitor peak - BU/mL median (IQR)	41.8 (15.0-97.0)	1	57.0 (20.0-202.0)	41.6 (14.0-81.4)	0.102‡
Inhibitor titer immediately before ITI - BU/mL median (IQR)	6.0 (2.8-12.8)	0	5.6 (1.5-12.8)	6.0 (2.9-12.8)	0.522‡
ITI characteristic
Age at start - years median (IQR)	7.0 (2.5-19.7)	0	7.4 (2.2-16.2)	6.7 (2.6-20.1)	0.833‡
Interval between inhibitor diagnosis and start - years median (IQR)	1.7 (0.6-8.9)	0	2.8 (0.6-8.9)	1.5 (0.6-9.0)	0.489‡
pdFVIII as first factor n (%)	98 (60.5 %)	1	17 (51.5 %)	81 (62.8 %)	0.237†
Need for intensification n (%)	64 (39.3 %)	0	14 (42.4 %)	50 (38.5 %)	0.677†
Need for prophylaxis with bypassing agents n (%)	107 (65.6 %)	0	26 (78.8 %)	81 (62.3 %)	0.075†
Bleedings/year median (IQR)	3.4 (1.7-6.8)	2	3.5 (1.7-10.7)	3.2 (1.7-6.4)	0.455‡
Inhibitor peak - BU/mL median (IQR)	25.3 (5.6-121.6)	2	23.6 (6.4-126.0)	25.3 (4.6-121.6)	0.880‡
Success n (%)	112 (68.7 %)	0	24 (72.7 %)	88 (67.7 %)	0.577†
Duration - years median (IQR)	2.6 (1.7-3.1)	1	2.6 (1.9-3.2)	2.6 (1.6-3.1)	0.710‡

Procedure	Number (%)
Central venous access (both insertions and removals)	18 (40.0 %)
Dental procedures (tooth extractions and others)	13 (29.0 %)
Radiosynoviorthesis	9 (20.0 %)
External ventricular drain insertion	1 (2.2 %)
Orchiopexy	1 (2.2 %)
Joint corticosteroid infiltration	1 (2.2 %)
Nasal cauterization	1 (2.2 %)
Cataract surgery	1 (2.2 %)

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Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) R. Dr. Diogo de Faria, 775 cj 133, 04037-002, São Paulo / SP - Brasil - São Paulo - SP - Brazil
E-mail: htct@abhh.org.br

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[TFN1] ^†
Pearson's χ² test.

[TFN2] ^‡
Mann-Whitney's U test

BU: Bethesda unit; F8: gene encoding the clotting factor VIII; IQR: interquartile range; ITI: immune tolerance induction; pdFVIII: plasma-derived factor VIII.