Avaliação de fatores associados à resposta ao tratamento de imunotolerância em pacientes com hemofilia A hereditária e inibidor

Abstract

Hemophilia A (HA) is a rare bleeding disorder resulting from the deficiency of clotting factor VIII (FVIII), due to mutations in the gene that encodes it (F8). Bleeding episodes manifest as spontaneous or post-traumatic, presenting mainly as intramuscular hematomas and joint bleeding (hemarthrosis), but can also affect vital organs. Thus, replacement with FVIII concentrate is necessary both to stop bleeding (episodic treatment) and to prevent it (prophylaxis). Currently, the most serious iatrogenic complication of HA treatment is the development of anti-FVIII neutralizing antibodies, known as inhibitors. They develop in up to 30% of people with severe HA (PwHA) and up to 5% of non-severe PwHA. In such cases, the use of bypassing agents should be instituted, either for episodic or prophylactic treatment. The only therapy currently available for eradication of inhibitors is immunotolerance induction (ITI). ITI is indicated for PwHA and inhibitor that interferes with the hemostatic activity of FVIII, therefore, requiring the use of bypassing agents. ITI consists of frequent infusions of FVIII concentrate to induce (re)tolerance and recovery of the FVIII hemostatic function, with success rates from 60% to 80%. In Brazil, since 2012, approximately 450 PwHA and inhibitor started ITI according to the Brazilian Protocol. This protocol establishes an initial regimen of low doses of FVIII three times per week and, in the absence of reduction in the inhibitor titer, the regimen is increased to high and daily doses. We took advantage of the availability of this large population of PwHA and inhibitor on ITI and proposed the BrazIT Study, which is a national multicenter study coordinated by the Faculty of Medicine of the Universidade Federal de Minas Gerais. The aim of the BrazIT Study was to assess predictors of response to ITI. PwHA and inhibitor who are about to start, have finished, or are under ITI were included in the 15 Hemophilia Treatment Centers participating in the study. Clinical and laboratory data were obtained from the pre- and during the ITI through analysis of medical records and interviews. Whole blood samples were collected and used for DNA extraction with exome analysis and immunological testing. This subproject of the BrazIT Study aims to identify clinical and immunological factors as potential predictors of response to IT. The detailed methodology of the study was published in the journal PLoS ONE in 2021. To date, 207 PwHA and inhibitor have been included. There were 9 (4.3%) withdrawns and 2 (1.0%) deaths during IT. While 33 (15.9%) are still under treatment, 163 (78.8%) completed treatment. Of this group, there were 50 (30.7%) failures, resulting in a success rate of 69.3% (113 successes). Another analysis evaluated whether the time interval between inhibitor detection and onset of ITI was associated with its outcome in 142 PwHA and high-response inhibitor (PwHA-HRi). The overall ITI success rate was 65.5%, with no difference between the first, second, third and fourth quartiles of the range (62.9%, 69.4%, 58.3%, and 71.4%, respectively), even after adjusting for potential confounders. We also evaluated whether switching from recombinant FVIII (rFVIII) to plasma-derived (pdFVIII) during ITI, in those PwHA-HRi that were not responding to the first, would impact the outcome. All PwHA-HRi who underwent change of the FVIII type (n = 8; 100%) failed. Finally, a systematic review with metaanalysis of 27 studies in 1,734 PwHA showed that, among the 20 potential determinants evaluated, a historical peak < 100 BU (Bethesda units)/mL (odds ratio [OR] 1.67, 95% confidence interval [95%CI] 1.35-2.07), pre-ITI inhibitor titer < 10 BU/mL (OR 1.78, 95%CI 1.40-2.26), and peak inhibitor during ITI < 100 BU/ mL (OR 2.66, 95%CI 1.87-3.79) were associated with ITI success. Thus, we conclude that IgG4 is a marker of ITI failure, that surgeries, switching from rFVIII to pdFVIII, and the time interval between the detection of an inhibitor and the onset of ITI were not associated with ITI outcome. However, historical peak < 100 BU/mL, pre-ITI inhibitor titer < 10 BU/mL, and inhibitor peak during ITI < 100 BU/mL were associated with ITI success.