Rituximab for the Primary Treatment of Denovo Extensive Chronic Graft Versus Host Disease (GVHD)
Rituximab is an attractive agent to bring to the upfront treatment of chronic graft-versus-host disease (cGVHD) due to its favorable toxicity profile, its proven efficacy in the treatment of steroid-refractory cGVHD, and its ability to serve as a steroid sparing agent in other autoimmune diseases. The investigators hope to demonstrate that Rituximab has significant activity in cGVHD when utilized early in the course of the process. In addition, the investigators hope to show that the early use of Rituximab may allow for the earlier discontinuation of immunosuppression while obviating the need for long courses of systemic corticosteroids, which should translate into reduced treatment-related morbidity and mortality associated with cGVHD.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Trial Evaluating the Safety and Efficacy of Rituximab as Primary Treatment for Extensive Chronic Graft Versus Host Disease|
- To estimate the rate of complete, partial and overall response of cGVHD to treatment. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]We will evaluate patients at 1, 2, 3, 6, 9, 12, 18 and 24 months from the start of treatment.
- To estimate the requirement for and duration of systemic corticosteroids [ Time Frame: 2 years ] [ Designated as safety issue: No ]Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
- Estimate the time to immunosuppression withdrawal [ Time Frame: 2 years ] [ Designated as safety issue: No ]We will evaluate patients at 1, 2, 3, 6, 9, 12, 18 and 24 months from the start of treatment. Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
- Estimate incidence of non-relapse mortality, disease-free and overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]Patients will be evaluated at 1, 2, 3, 6, 9, 12, 18 and 24 months after the start of treatment.
|Study Start Date:||April 2011|
|Estimated Study Completion Date:||January 2015|
|Estimated Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
all patients will receive Rituxan for the treatment of newly diagnosed chronic GVHD
Rituximab 375 mg/m2/dose x 4 weekly doses on days 1, 8, 15 and 22 and then at 3, 6, 9 and 12 months.
Other Name: Rituxan
Although allogeneic hematopoietic stem cell transplantation (HSCT) remains an important curative therapy for many patients with hematological malignancies, treatment-related morbidity and mortality continue to be a major challenge. Chronic GVHD remains a major complication following allogeneic HSCT, with more than half of patients being affected. Although cGVHD has been associated with decreased relapse risk due to the well documented graft-versus-malignancy effect, it is also associated with significant adverse consequences in terms of morbidity, mortality, quality-of-life, and treatment costs associated with HSCT.
Rituximab has been investigated in a small number of patients with refractory cGVHD using the standard regimen of 375 mg/m2/week for 4 weeks. Ratanatharathorn et al. documented a sustained response in four of eight patients with steroid-refractory cGVHD with diffuse or localized sclerodermatous manifestations. Similarly, Canninga-vanDijk et al. and Okamoto et al. observed cases with clinical, laboratory and histological improvement after Rituximab treatment. Cutler et al. reported the results of their phase I-II study with Rituximab in 21 patients with steroid-refractory cGVHD. Treatment was well tolerated, and toxicity limited to infectious events, without any hematological toxicities and only a significant reduction in circulating immunoglobulins documented after therapy. Objective responses were documented in 70% of patients (including 10% complete response) primarily for those with skin and musculoskeletal involvement, allowing tapering, and in some cases withdrawing, of previous immunosuppressant therapy. A correlation between clinical response and decrease in the titre of antibodies against Y chromosome-encoded minor HLA antigens was shown. The results of these preliminary studies highlight the potential therapeutic activity of Rituximab on some cGVHD manifestations and a particularly high efficacy for skin involvement, including scleroderma. Recently, Zaja et al. confirmed the activity of Rituximab in refractory cGVHD in a larger series of 38 patients. Treatment was generally well tolerated and nearly 60% and 50% of patients had a clinical improvement of their skin and mouth manifestations, respectively. The median time-to-response was nearly 2 months and in some cases responses were durable. Responses were also detectable in some patients with eye, liver, lung, gut and joint involvement, allowing reduction and/or suspension of previous baseline immunosuppressive therapy in a significant number of patients
|Contact: Stacey Brown, BAfirstname.lastname@example.org|
|Contact: Linda Vrooman, RNemail@example.com|
|United States, Georgia|
|Atlanta, Georgia, United States, 30342|
|Contact: Stacey Brown, BA 404-851-8238 firstname.lastname@example.org|
|Contact: Linda Vrooman, RN 404-851-8523 email@example.com|
|Principal Investigator: Scott R Solomon, MD|
|Sub-Investigator: Asad Bashey, MD, PhD|
|Sub-Investigator: H. Kent Holland, MD|
|Sub-Investigator: Lawrence E Morris, MD|
|Principal Investigator:||Scott R Solomon, MD||Blood and Marrow Transplant Group of Georgia|