Alloantibodies in previously untreated hemophilia A patients: the role of environmental factors

Figures & data

Table 1. Age and intensity at first FVIII exposure and inhibitor development in severe hemophilia A patients: analysis of the most important published studies

Author, year (reference)	Study design (no. patients)	Main findings
Lorenzo, 2001^9	Retrospective cohort study (62)	Cumulative inhibitor incidence at 3 years from the first FVIII exposure was 41% in patients starting therapy before the age of 6 months, 29% in patients starting therapy between 6 and 12 months of age, and 12% in those starting therapy beyond 1 year (P = 0.03). At multivariate analysis, the age at initial treatment was an independent variable.
Van der Bom, 2003^10	Retrospective cohort study (81)	Cumulative inhibitor incidence at 100 exposure days was 34% in patients starting therapy before the age of 6 months, 20% in patients starting therapy between 6 and 12 months of age, 13% in those starting therapy between 1 and 1.5 years, and 0% in those starting therapy beyond 1.5 years (P = 0.03).
Santagostino, 2005^11	Case–control study (108)	A trend was found for an increased risk (OR 2.8; 95% CI 1.0–7.6) of inhibitor development in children first treated at a young age (≤11 vs. >16 months); however, this was not confirmed after adjusting for genetic factors.
Goudemand, 2006^12	Retrospective cohort study (148)	At multivariate analysis, children treated for the first time after 12 months of age showed fewer inhibitors (RR 0.3; 95% CI 0.1–0.7) than those treated before 6 months of age.
Chalmers, 2007^13	Retrospective cohort study (348)	At univariate analysis, a significant difference in inhibitor development and age at first exposure across all age groups was observed (20–26% at ages 0–18 months vs. 9% at ages >18 months, P = 0.018). At multivariate analysis, only FVIII gene mutation remained significant.
Gouw, 2007^14	Retrospective cohort study (366)	At univariate analysis, but not at multivariate analysis, age at first treatment (<1 month versus >18 months) was associated with an increased RR of inhibitor development (2.7 [95% CI 1.2–5.9] for all inhibitors and 2.4 [95% CI 1.0–5.6] for high-titer inhibitors). Surgical procedures and peak treatment moments at the start of treatment increased inhibitor risk (RR 3.7; 95% CI 2.0–7.1 and 3.3; 95% CI 2.1–5.3, respectively).
Gouw, 2007^15	Combined analysis of four registration studies (236)	Age at first exposure was not associated with inhibitor development. Peak treatment moments and surgical procedures were related to an increased inhibitor risk (RR 1.6; 95% CI 1.0–2.6 and 2.7 95% CI 1.3–5.7, respectively)
Maclean, 2011^16	Retrospective case–control study (78)	No association was found between inhibitor development and age at first FVIII exposure. High-intensity treatment increased inhibitor risk around 2.5 folds.

RR, relative risk; OR, odds ratio.

Table 2. Summary of the main results of the published comparative studies and systematic reviews comparing the inhibitor development with the use of rFVIII or pdFVIII concentrates in PUPs with severe hemophilia A

First author, year^ref. (study design – no. of pts./study)	Type of FVIII	Overall inhibitor incidence mean % (range), P		High-responding inhibitor mean % (range), P
Comparative studies
Mauser-Bunschoten, 2001^28 (PS, 81)	CP-pdFVIII	23.7	NS	NA	NA
	MoFVIII-rFVIII	22.7		NA
Kreuz, 2002^29 (PS, 72)	pdFVIII	45.7	NS	37.1	NS
	rFVIII	36.4		36.4
GTH-PUP, 2003^30 (PS, 112)	pdFVIII	21	NS	NA	NA
	rFVIII	36		NA
Goudemand, 2006^12 (RS, 148)	pdFVIII	11.3	0.049	4.8	NS
	rFVIII	31.4		15.1
Chalmers, 2007^13 (RS, 348)	pdFVIII	13.6	0.009	9.8	NS
	rFVIII	27.3		15.1
CANAL, 2007^31 (RS, 316)	pdFVIII	21.5	NS	17.8	NS
	rFVIII	29.3		23.8
Systematic reviews
Wight, 2003^32 (8 RS, 13 PS)	pdFVIII	6.8 (0–12.4)	NA	1.4 (0–2.5)	NA
	rFVIII	37.5 (36–38.7)		15.1 (11.3–18)
Iorio, 2010^34 (5 RS, 19 PS)	pdFVIII	14.3 (10.4–19.4)	<0.001	9.3 (6.2–13.7)	0.004
	rFVIII	27.4 (23.6–31.5)		17.4 (14.2–21.2)
Franchini, 2012^35 (25 PS)	pdFVIII	21 (14–30)	NS	14 (8–25)	NS
	rFVIII	27 (21–33)		16 (13–20)

NA, nota available; RS, retrospective; PS, prospective; NS, not significant; CP, cryoprecipitate; Mo, monoclonally purified.

Table 3. Ad hoc quality score of the studies included in the meta-analysis by Franchini et al.³⁵ (unpublished data)

Author, year (reference)	Population size (n)	Follow-up Median (range)	Exposure days Median (range)	Definition of severe hemophilia	Inhibitor lower limit (BU)	Pharmacokinetic study	Inhibitor screening frequency	Total score
Plasma-derived FVIII concentrates
Lusher, 1990, 1991^Citation36,Citation37	25	3 y	NA	<1%	NA	NA	6 months	7
Ehrenforth, 1992^38	27	8 (0.08–15.25) y	NA	<1%	NA	NA	Every 20th ED	8
Ljung, 1992^39	77	2–22 y	NA	<1%	NA	NA	NA	8
Addiego, 1992^40	30	29 (9–48) m	NA	<1%	NA	5 patients	3 months	9
De Biasi, 1994^41	48	8.5 (0.8–15.5) y	97 (2–753)	<1%	0.8	NA	>annually	10
Yee, 1997^42	37	83 (15–113) m	200 (40–700)	<2%	NA	NA	>annually	10
El Alfy, 2000^43	25	3 y	NA	<1%	1.0	NA	6 months	8
Mauser-Bunschoten, 2001^28	59	14.5 (1.8–23.4) y	NA	<1%	1.0	NA	0.7–2 per year	10
Kreuz, 2002^29	35	23 y	270 (1–3051)	<1%	0.6	NA	Every 20th ED	13
Recombinant FVIII concentrates
Kreuz, 2002^29	11	23 y	270 (1–3051)	<1%	0.6	NA	Every 20th ED	13
Bray, 1994^44	72	7.3 y	94	<2%	0.6	All patients	3 months	15
Gruppo, 1998^45
Goodeve, 2000^46
Rothschild, 1998^7	50	32 (9–74) m	64 (2–840)	<1%	0.6	NA	>6 months	10
Lusher, 1993, 2004^Citation48,Citation49	65	8 y	126 (1–712)	<2%	0.6	38 patients	3 months	15
Yoshioka, 2003^50	31	49.2 (11–80) m	NA	<1%	NA	NA	3 months	8
Giangrande, 2002^51	19	2 y	85 (5–272)	<1%	0.6 (Nijmegen)	All patients	3–4 ED unitl 20 ED, then every 10 ED until 50 ED, then every 3 months	15
Kreuz, 2005^52	37	3.5 y	114 (4–478)	<2%	0.6	All patients	3-4 ED unitl 20 ED, then every 10 ED until 50 ED, then every 3 months	15
Oldenburg, 2006^53
Musso, 2008^54	13	3 y	187 (121)*	<2%	NA	NA	NA	7
Lusher, 2003,2005^Citation55,Citation56	101	6 y	197 (1–1466)	<2%	0.6 (Nijmegen)	11 patients	3 months	16
Courter, 2001^57
Pollmann, 2007^58	16*	24.7 (16.4) m*	142 (93–180)	<2%	0.6	NA	NA	9

m, months; y, years; ED, exposure days; NA, not available; BU, Bethesda Units.

*Mean (SD)

The seven-item score includes: (a) Population size (1: 10 – <20 patients; 2: 20–50 patients; 3: >50 patients), (b) Median follow-up (1: <2 years; 2: 2–5 years; 3: >5 years), (c) exposure days (1: <50 days; 2: 50–100 days; 3: >100 days), (d) definition of severe hemophilia (1: <2% FVIII:C; 2: <1% FVIII:C), (e) inhibitor detection lower limit (1: 0.8 BU or more; 2: 0.6 BU; 3: 0.6 BU [using Nijmegen modification]), (f) pharmacokinetic study (FVIII recovery and half-life). (1: In a subgroup of patients; 2: All patients), (g) inhibitor screening frequency (1: >3 months [≥20 ED]; 2: every 3 months; 3: every 5 ED until the 20th ED, every 10 ED until the 50th ED, then every 3 months.). The minimum score was 0 and the maximum score was 19. A score between 13 and 19 points identified good quality studies; a score between 7 and 12 points identified medium quality studies while low-quality studies were those that reached a score between 0 and 6 points.

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