Is rituximab effective in acquired von Willebrand syndrome?

Abstract

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder associated with monoclonal gammopathy, lymphoproliferative or myeloproliferative syndromes, or cardiovascular disease. Low levels of plasma von Willebrand factor (VWF) are the result of the accelerated removal of protein from plasma through the action of different pathogenic mechanisms (Federici et al, 2000; Veyradier et al, 2000). Therapeutic options include desmopressin (Minirin®), factor VIII (FVIII)/VWF concentrate and intravenous immunoglobulin (IVIg), corticosteroids, immunosuppressive agents or chemotherapy (Federici et al, 2000). Treatment of the underlying disease may improve AVWS. Rituximab (Mabthera®), a chimaeric anti-CD20 monoclonal antibody, seems to have some efficacy in the treatment of patients with acquired haemophilia A (Federici et al, 1998). We report two cases of AVWS associated with monoclonal gammopathy of uncertain significance (MGUS) treated with rituximab. Patient 1, a 91-year-old male, was diagnosed with AVWS based on the following: activated partial thromboplastin time (aPTT) ratio 1·36, FVIII 6%, VWF activity 10% and antigen 10%, platelet occlusion time >300 s for collagen-adrenaline and collagen-ADP, IgGκ monoclonal gammopathy (3 g/l), increased VWF-propeptide (197%) and anti-VWF positive for IgG. The patient was treated with IVIg (Tégéline®) for elective surgery, Wilfactin®, Factane® and IVIg (Tégéline®) (LFB, Courtaboeuf, France) for haematemesis associated with ulceration of the duodenal bulb, and monthly IVIg to maintain a stable haemoglobin level. Concern regarding the potential risk of renal failure prompted the use of rituximab (two injections of 350 mg/m² each), but this was ineffective. The second male patient was 43 years old when AVWS was identified: aPTT ratio 1·51, FVIII 14%, VWF activity <10%, VWF antigen 16%, no detection of anti-VWF antibody, presence of IgGκ monoclonal gammopathy (4 g/l), VWF-propeptide not determined. The patient was treated with: desmopressin (Minirin®) for fibroscopy (ulceration of the duodenal bulb) and monthly IVIg for 2 years for chronic anaemia. In an attempt to correct the AVSW, rituximab was initiated (four injections of 350 mg/m² each), but was ineffective. IVIg remains the therapy of choice in AVWS for the prevention of bleeding during elective surgery or to treat bleeding in addition to desmopressin and/or VWF concentrate for the first few days pending efficacy of IVIg (Federici et al, 1998). As compared with acquired haemophilia, which is always due to auto-antibodies against FVIII, the pathogenic mechanisms underlying AVWS are more heterogeneous. Previous reports have shown that rituximab is an option for the correction of acquired haemophilia (Stachnik, 2006). For our two patients with AVWS, rituximab was initiated 1 month after the last administration of IVIg, as an alternative treatment, expecting a correction of their disease and the FVIII/VWF complex. However, no change in the level of FVIII/VWF complex was observed. Rituximab was ineffective in a 64-year-old man with AVWS and a history of rectal bleeding after prostate biopsy (Moll et al, 2003). Rituximab was also reported to be ineffective in IgGκ-MGUS patients, administered alone (Grimaldi et al, 2008) or in combination with melphalan and prednisone (Agarwal et al, 2004). None of the proposed mechanisms appeared to be disease-specific (Federici, 2008; Tiede et al, 2008). It would be interesting to understand the different mechanisms of action of IVIg and rituximab in acquired haemophilia and in AVWS, because high-dose IVIg seems more effective in AVWS than in acquired haemophilia, and rituximab seems more effective in acquired haemophilia than in acquired von Willebrand disease.