Rituximab for the Primary Treatment of Denovo Extensive Chronic Graft Versus Host Disease (GVHD)
Condition: Chronic Graft-versus-host Disease
MeSH terms: Bronchiolitis Obliterans Syndrome; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Rituximab
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Rituxan
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic Graft versus Host Disease; allogeneic stem cell transplant