Successful eradication of acquired factor-VIII-inhibitor using single low-dose rituximab

It was with great interest that we read the recent recommendations regarding the treatment of acquired hemophilia A published in Haematologica1 and followed the subsequent discussion.2,3 The described treatment algorithm for this disease, which occurs at an incidence of 1.5/million/year,4 stresses the importance of early eradication of the acquired fVIII-inhibitor. Using prednisolone alone or in combination with cyclophosphamide, this approach will be successful in 30–50% of affected individuals.5 As Huth-Kühne pointed out, the CD20-antibody rituximab may be an attractive alternative in non-responders or patients with contraindications to steroids.6 However, concerns have been raised because of rituximab side-effects including associations with progressive multifocal leukencephalopathy (PML).7 Furthermore, as Mannucci et al.2 emphasized, the use of this drug is hampered by its substantial costs. Restricting the administered dose to the lowest effective level, seems to be a reasonable strategy to minimize potential risks and costs of rituximab treatment.

Figure 1.Clinical course overview. Time since diagnosis in months (x-axis). fVIII-inhibitor titer in Bethesda Units (BU) (left y-axis). B-cell proportion (%) (right y-axis). R: time of rituximab application.

We report a 66-year old male AHA-patient successfully treated with single low-dose rituximab. The patient presented with multiple hematomas and severe anemia after recovering from a respiratory infection. Prolonged activated partial-thromboplastin-time (aPTT) in combination with undetectable fVIII-activity due to an fVIII-inhibitor was observed. There was no clinical history of any prior hemorrhages nor a family history of bleeding. Clinical and imaging examinations could not reveal any pathological findings suggesting an idiopathic cause of AHA. Prednisolone (1 mg/kg) was started immediately and 2 units of packed red blood cells had to be administered. Afterwards, bleeding ceased, correlating with an increase in fVIII-activity to 28%. Steroids were completely tapered over the next weeks and the patient was lost to follow-up. However, during the following year the patient experienced recurrent episodes of minor bleeding.

Seventeen months after the first onset of AHA, he again presented at our institution for follow-up. He reported no spontaneous bleeding episodes; however, fVIII-activity was 15% translating into an fVIII-inhibitor of 133 BU (Bethesda Units). Two months later, severe limb-bleeding requiring surgical treatment occurred after a minor accident. FVIII-inhibitor could still be detected at high levels (79 BU). Because of impaired wound-healing, steroids were deemed contraindicated. Therefore, given our experience with patients with auto-immune diseases other than AHA,8 inhibitor-eradication treatment was started with a single flat dose of 100 mg rituximab. Treatment was well tolerated and three weeks later complete B-cell depletion could be demonstrated (Figure 1). There was no reoccurrence of significant bleeding and even an accident was tolerated without complications. At last presentation, nearly ten months after rituximab treatment, the patient had only a low residual fVIII-inhibitor activity, in spite of a normal B-cell count. FVIII-levels stabilized at a level of 15 to 20% and aPTT was never again found to be prolonged after rituximab treatment.

The clinical course of our patient demonstrates that complete B-cell depletion can be achieved with low-dose rituximab in AHA. We are aware that given the persistently low fVIII-level, our patient does not meet the strict criteria for inhibitor eradication proposed by Huth-Kühne. On the other hand, we have to acknowledge that he experienced no further bleeding and had inhibitor-titers near the detection limit. We, therefore, believe that future clinical trials should incorporate this low-dose regimen rather than the classical lymphoma-dose (e.g. 375 mg/m) in the treatment of acquired hemophilia A.