Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

Abstract

Haemophilia A is a rare congenital bleeding disorder caused by a deficiency of blood coagulation protein factor VIII (fVIII). Prophylactic fVIII infusions are the standard of care for the prevention of bleeds and their sequela. 1 However, 30% of individuals with severe deficiency will develop neutralizing antibodies, called inhibitors, against fVIII. 2 Most patients who develop inhibitors, particularly individuals with high titre inhibitors (titres ≥ 5 Bethesda units (BU) per mL), require immune tolerance induction (ITI) consisting of frequent and often high dose fVIII to induce peripheral tolerance. ITI is the standard of care for eradicating inhibitors with reported success Abstract Introduction: The formation of neutralizing antifactor VIII (fVIII) antibodies, called inhibitors, is the most common complication in modern haemophilia A care. Novel non-factor replacement therapies, such as emicizumab, have sought to address the limitations of bypassing agents for bleeding management in patients with inhibitors.However, immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Aim:The aim of this study was to review a case series of paediatric patients with haemophilia A and inhibitors who have received ITI for inhibitor eradication concomitantly with emicizumab prophylaxis for bleeding prevention.Methods: Single institution retrospective chart review of paediatric patients with severe haemophilia A receiving ITI and emicizumab.Results: Seven patients were included in this cohort. Six patients used three different recombinant fVIII products at 100 IU/kg three times per week, and one patient used a plasma-derived fVIII product at an initial dose of 50 IU/kg three times per week.

Emicizumab treatment and monitoring in a paediatric cohort: real‐world data

“…28 Prospective studies will be necessary to compare treatment outcomes of a combined ITI and emicizumab regimen with a standard ITI or emicizumab prophylaxis-only regimen and to investigate whether emicizumab prophylaxis modifies the immunologic response to FVIII. 27 Breakthrough bleeds occurred in 50% of the patients in our group, which is slightly higher than rates reported in previous studies. 11,23,29 Principally, our cohort has been followed for a relatively long period, and this could explain the greater number of documented bleeds.…”

Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

“…41 Prophylactic use of emicizumab may be used in patients undergoing ITI as supportive treatment to minimize bleeding events. This has already been successfully tested 95 and is considered a potential new approach for the management of inhibitor patients. 96 Subsequently, instead of continued FVIII replacement, patients could be switched to emicizumab-only treatment; however, the question of whether completed ITI necessitates the continued administration of FVIII to maintain tolerance remains unanswered.…”

The Art of Detecting Antibodies against Factor VIII

“…11 NBA:CSB can be used if samples contain emicizumab because FVIII:CSB contains bovine proteins and is insensitive to the drug. 12 Alternatively, anti-idiotypic antibodies can be used to neutralize emicizumab in the sample. 13 Other Conditions that Interfere with the Bethesda Assay Pharmacological anticoagulants that prolong the APTT can cause false-positive results in the NBA and should be avoided at the time of sampling.…”

“…NBA:CSB showed an overall good correlation with results from the NBA, could eliminate some low-titer, false-positive results, 16 is expected to be less sensitive to LA, 17 and is insensitive to the effects of emicizumab. 12 Imidazole-buffered bovine serum albumin as a sample diluent may improve specificity as compared with FVIII-deficient plasma. 18…”