Anti-CD20 therapy for the treatment of
chronic graft versus host disease.

Allogeneic stem cell transplantation (allo-SCT) is the treatment of choice of many hematological malignancies, owing to the graft-versus-leukemia (GVL) effect from the allogeneic donor T cells. Unfortunately, the positive effect of GVL is counterbalanced by graft-versus-host disease (GVHD), a major complication following allo-SCT of which the resultant multi-organ damage and immune deficiency significantly impair overall survival after SCT. GVHD can be distinguished in an acute and a chronic form. Acute GVHD is a distinctive syndrome of dermatitis, hepatitis and enteritis, while the term chronic GVHD describes a more pleiotropic syndrome. 60-70% of all patients receiving an allo-SCT and surviving beyond day 100 develop chronic GVHD. In our own institute (UMC Utrecht), the incidence of chronic GVHD is 60%, while 44% of all patients develop extensive disease. The first line treatment of extensive chronic GVHD consists of steroids with or without the addition of cyclosporin, depending on the existence of a thrombocytopenia (<100 x 10exp9/L). However, 58% of all patients with extensive chronic GVHD is refractory to steroid treatment. Although the contribution of donor T cells to the development of both acute and chronic GVHD is beyond doubt, the role of B cells is much less well defined. However, two observations suggest that B cells do contribute to GVHD. In the first place, autoantibodies can be detected in 15-90% of chronic GVHD patients. Secondly, three small-scale clinical studies have demonstrated that in vivo depletion of B cells with the CD20-specific Ab rituximab resulted in amelioration of chronic GVHD symptoms in heavily pretreated steroid-refractory patients. Preliminary analysis of skin and liver biopsies taken during chronic GVHD revealed the deposition of IgG Ab on epithelial cells and the basal membrane. Together, these findings prompt us to better define the role for B cells in the development of chronic GVHD. This improved understanding will serve two purposes. In the first place, a better insight into the pathogenesis of chronic GVHD is essential to develop new treatment modalities. In addition, development of novel prognostic markers that can predict the occurence of chronic GVHD may result in a risk-adapted prevention strategy of GVHD.

B cells contribute to the development of cGVHD.

Treatment with Rituximab once a week, for 4 weeks.