Eradication of factor viii inhibitors in patients with mild and moderate hemophilia A

Abstract

In hemophilia A, up to 25% of new anti-factor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease [1]. Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician’s management decisions. In a case series, 8/26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; 2 successful, 2 unsuccessful and 4 partially successful [2]. In a systematic review of the literature, 12/16 patients with mild or moderate hemophilia responded to rituximab for treatment to eradicate the inhibitor [3]. To increase our understanding of treatment options for inhibitor eradication in patients with mild or moderate hemophilia A complicated by an inhibitor, a secondary analysis of clinical and treatment characteristics in a cohort of 36 patients with mild or moderate hemophilia A and inhibitor was undertaken. In multivariate analyses, rituximab alone (n=6) and other immune modulating treatments alone (n=2) were significantly associated with an increased likelihood of inhibitor clearance [hazard ratio (HR) of 4.4 (95% CI 1.06–20.03) and 10.21 (95% CI 1.17–78.28), respectively] whereas ITI alone (n=9) was not [HR 1.35 (95% CI 0.44–4.07)].

Toward optimal therapy for inhibitors in hemophilia

“…In a series of 36 cases of mild or moderate hemophilia A complicated by an inhibitor, multivariable analysis did not demonstrate any benefit of ITI. 50 This observation is consistent with prior poor responses reported by Hay et al 51 Rituximab has been used more commonly in this group and, in contrast to severe hemophilia A, those with mild/moderate hemophilia A appear to have a better and more durable overall response rate; however, how this compares to observation alone in this population remains unknown. 50 …”

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

“…The management of FVIII inhibitors in patients with mild haemophilia A is a challenge due to the older age at onset and seeming lower effectiveness of conventional ITI . Nevertheless, in the INSIGHT study (International Study on Etiology of Inhibitors in Patients with a Moderate or Mild Form of Hemophilia A, Influences of Immuno‐Genetic & Hemophilia Treatment Factor), which included 101 non‐severe patients with haemophilia A and inhibitors, inhibitors disappeared in the majority of patients (72/101; 72%), either spontaneously (51/73; 70%), or after eradication treatment (21/28; 75%) .…”

“…Nevertheless, in the INSIGHT study (International Study on Etiology of Inhibitors in Patients with a Moderate or Mild Form of Hemophilia A, Influences of Immuno‐Genetic & Hemophilia Treatment Factor), which included 101 non‐severe patients with haemophilia A and inhibitors, inhibitors disappeared in the majority of patients (72/101; 72%), either spontaneously (51/73; 70%), or after eradication treatment (21/28; 75%) . In patients with mild haemophilia A, FVIII inhibitors may share features with FVIII autoantibodies that occur commonly in acquired haemophilia A, and this may explain why immunosuppressive therapy can be effective in reducing the inhibitor titre in some patients …”

Management of adult non‐severe haemophilia A patients with inhibitors: a practice‐pattern survey

“…Limited data are available on ITI in patients with NSHA, although in general, this approach appears to be less effective than in SHA [4,5]. Limited data are available on ITI in patients with NSHA, although in general, this approach appears to be less effective than in SHA [4,5].…”