Environmental Risk Factors of Inhibitor in Mild/Moderate Hemophilia A Patients Included in the FranceCoag Network

Abstract

Abstract 1213▪▪This icon denotes a clinically relevant abstract Introduction:The proportion of inhibitors is lower (5–10%) in mild/moderate hemophilia A (MM-HA) than in severe HA (20–35%) and the associated risk factors have been less studied. FVIII deficiency is due to a missense mutation of F8 gene in most of MM-HA patients (pts). Several studies showed that specific mutations are associated with a higher incidence of FVIII inhibitor. On the other hand, two recent studies performed in limited populations of pts identified intensive replacement therapy and age over 30 years as risk factors of inhibitor in MM-HA. An open multicenter prospective cohort of hemophilia pts was launched in France in 1994 and extended to all Hemophilia Treatment Centers (HTC) through the FranceCoag Network (FCN) in 2003 - seehttp://www.francecoag.org/for protocol and participating centers. 5615 male hemophilia pts were included and the objective of the present study was to better identify environmental risk factors of FVIII inhibitor in MM-HA by studying this large cohort. Methods:Clinical and biological data were collected and transmitted via Internet for each patient every year or less frequently if irregular follow up. All information was checked automatically and monitored on a regular basis in HTC. Severity of HA was defined according to FVIII:C level (moderate 1–5; mild 6–40 IU/dL). Positive inhibitor was defined by two consecutive samples with titer >0.6 Bethesda Unit (BU). All unclear cases were reviewed on a collegial basis. The duration exposure from the initiation of FVIII treatment was analyzed and the associations between four fixed factors and the development of FVIII inhibitor were assessed. Results:In July 2011, 2924 MM-HA pts were recorded in FCN including 2055 (70%) who had been previously treated with FVIII. The median duration of exposure was 12.8 years (IQR: 4.0–23.8), including 4.4 years (IQR: 1.0–7.4) after inclusion in the FCN, and corresponding to 30,620 and 10,517 person-years respectively. An inhibitor was diagnosed in 99 pts, including 40 with a high titer (>5BU). These inhibitors occurred at a median age of 31.7 years (IQR: 9.0–50.8), a median period of 6.8 years (0.4–24.3) following the first infusion of FVIII and a median number of 30 Cumulative Exposure Days (CED) (17–55). The FVIII inhibitor occurred at an earlier age in moderate HA pts (n=56) compared to the 43 mild HA pts (Table 1), but after a longer exposure time and a higher number of CED. The cumulative incidence of inhibitor was 4.5% after 20 years of exposure (95%CI: 3.5–5.8). The incidence of inhibitor was significantly higher in moderate HA pts and those whose treatment has been initiated after 1990 (Table 2). Age and type of FVIII concentrate at the first infusion don’t appear to be associated with the incidence of inhibitor.Table 1Characteristics of MM-HA pts at disclosure of inhibitor according to the severity of hemophiliaModerate (n=56)Mild (n=43)pMedianIQRMedianIQR(Kruskal-Wallis)Age (years)23.38.4–38.844.615.0–62.50.021Duration of exposition to FVIII (y)8.23.8–25.22.90.1–24.30.047CED:16 missing values (MV)4021–662614–400.028High titer (>5BU) Nb (%)23(41)17(40)0.877Table 2Cofactors associated to inhibitor incidence since first infusion of FVIIICofactorsNNb of inhibitorsCI at 20 years*Multivariate analysis (Cox model)(%)adj. RR95%CIpSeverity of hemophilia:7 MV0.0011–5 IU/dL (FVIII:C)755566.216–14687354.80.70.5–1.115–4060681.10.20.1–0.4Age at 1st infusion (years): 23 MV0.2840–4662304.715–19680354.51.10.7–1.9>=20690324.21.50.9–2.6Calendar period at 1st infusion: 23 MV**0.014<1990775481.211990–99510284.92.91.4–6.22000–11747215.33.51.3–9.4Type of FVIII at 1st infusion:134 MV**0.314Plasma derived1153632.01Recombinant768275.51.50.7–3.1*Cumulated Incidence (CI)**CI at 10 yearsDisclosures: d'Oiron:Bayer, Baxter, CSL Behring, Novonordisk: Funding for participation to congresses; Fees for participation as speaker at symposium; Fees for participation to boards. Calvez:LFB: Funding for participation to congresses. Conclusion:The apparent increase in incidence of inhibitor in MM-HA pts who were treated by FVIII after 1990 could be related to an evolution of practices (i.e. greater frequency of invasive procedures and/or more intensive treatment) and/or more frequent testing for inhibitor. These time-varying factors systematically recorded in the FCN will be analyzed taking into account only the observation period after enrolment in the cohort. In addition, the F8 gene defect is now recorded in all pts of the FCN, and this should allow us to better evaluate the respective role of genetic and environmental risk factors in the development of FVIII inhibitor in MM-HA.