Treatment Outcome of Steroid-Refractory Chronic Graft-Versus-Host Disease with Weekly Rituximab Followed by Maintenance Rituximab: a KSBMT Multicenter Phase II Study.

The mainstay of treatment for chronic graft-versus-host disease (GVHD) is steroid. However, there is limited treatment option for steroid-refractory chronic GVHD. Although the pathogenesis of chronic GVHD is still uncertain, the possible relation of auto-antibodies with chronic GVHD (Patriarca F, et al. Exp Hematol 389-96, 2006) and the result from a previous pilot study (Cutler C, et al. Blood 756-762, 2006) suggested that a treatment strategy targeting against B cells might become another effective therapy for chronic GVHD. Thus, we performed a study to determine the efficacy of rituximab (Mabthera®, Roche), an anti-CD20 monoclonal chimeric antibody in patients with steroid-refractory chronic GVHD.

This is a multicenter, open-labeled prospective phase II study performed by the Korean Society of Blood and Marrow Transplantation (NCT00472225). Patients should be diagnosed as chronic GVHD according to the criteria for clinical trials in chronic GVHD proposed by National Institutes of Health Consensus Development Project (Filipovich AH, et al. Biol Blood Marrow Transplant 945-56, 2005). The steroid-refractoriness was defined as the same severity during the last one month while patients received the equivalent of prednisone ≥0.5mg/kg per day or 1mg/kg every other day at least for 30 days or longer. The treatment schedule consists of induction (rituximab 375mg/m² weekly IV for 4 consecutive weeks) and maintenance (rituximab 375mg/m² monthly IV for 4 consecutive months). The response and the quality of life (SF36 questionnaire) were evaluated during the follow-up.

37 patients (20 male, 17 female) were evaluated, and their median age was 29 years (range 8-57 years, 7 patients from pediatrics and 30 from internal medicine). The time interval between transplantation and rituximab treatment was from 4.0 to 45.7 months. The most commonly involved organs were skin, oral cavity, eyes and lungs. The average number of involved organ per each patient was three and their average severity was grade 2-3. The median potential follow-up was 12.3 months (95% confidence interval: 12.06-12.54 months). The maximum response during follow-up was as follows: 8 complete response (21.6%), 22 partial response (59.5%), 6 no response (16.2%), and 1 disease progression (2.7%). Thus, the overall response rate was 81.1%. The dosage of steroid was reduced in all responders including complete withdrawal of steroid. The quality of life was improved in terms of physical health and mental/emotional health after treatment. However, 5 responders showed the progression of disease activity during follow-up, and infectious complications were life-threatening, thus, 8 patients died due to infections including pneumonia. The involvement of skin and oral cavity showed better response than the involvement of lungs and eyes.

The weekly administration of rituximab followed by monthly maintenance rituximab may be an effective treatment for steroid-refractory chronic GVHD, however, the active prophylaxis against infection should be considered.

No relevant conflicts of interest to declare.