A Phase II Study of Rituximab Combined With Prednisone for the Initial Treatment of Chronic Graft Versus Host Disease
Host antigen-presenting cells (APC) have an important role in the pathogenesis of chronic
graft-versus-host disease (C-GVHD). B cell antigen-presenting cells may also be important in
activating T cells in vivo. In a murine leukemia model, B cells have been shown to be
important APCs in T cell responses. Rates of C-GVHD were shown to lower in a B cell
deficient murine model when compared to mice that received rabbit immunoglobulin, and the
rate of C-GVHD was even lower if grafts were depleted of B cells. It would appear that B
cells have an important role as APCs in the pathogenesis of C-GVHD.
The chimeric anti-CD20 antibody Rituximab has been demonstrated to have activity in
steroid-refractory graft versus host disease in a few small retrospective studies. Previous
evidence in indolent lymphoma has demonstrated that Rituximab is a potent B-cell depleting
agent. These observations suggest that B-cell depletion in graft versus host disease may be
an effective therapy. Rituximab is currently being evaluated in two separate phase II
studies currently enrolling patients who have had an allogeneic stem cell transplant
(allo-SCT) or have developed GVHD.
The Dana Farber BMT program has recently published a phase II study examining the safety and
effectiveness of rituximab monotherapy in the setting of steroid-refractory GVHD. Rituximab
was administered weekly at the standard dose of 375 mg/m2. The clinical response rate was
70% and responses were limited to patients with cutaneous and musculoskeletal manifestations
of C-GVHD. Median corticosteroid doses improved from 40 mg/day to 10 mg/day. The BMT program
at Stanford is enrolling patients in a phase II study examining the impact of 4 weekly doses
of 375 mg/m2 of Rituximab given starting on day +56 following allo-SCT in patients with
chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) in an attempt to prevent
the development of subsequent GVHD.
These two studies will provide important phase II data regarding the safety and efficacy of
Rituximab in the prevention of GVHD and the treatment of steroid-refractory GVHD. Another
area of interest would be the initial treatment of GVHD. Although there is no universally
recognized standard of care, corticosteroids form the backbone of treatment for GVHD and are
either given as single agents or part of a combination therapy strategy with Cyclosporine A
(CsA), Tacrolimus (FK506) or mycophenolate mofetil (MMF).
We propose a phase II study of rituximab in combination with prednisone as primary therapy
for C-GVHD.
Interventional
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The efficacy of the combination of rituximab and prednisone as initial therapy for C-GVHD, which is defined as discontinuation of immunosuppressive therapy at 12 months with resolution of reversible manifestations of C-GVHD
12 months
No
John Kuruvilla
Principal Investigator
University Health Network, Toronto
Canada: Ethics Review Committee
OZM-009 (GVHD-R01)
NCT01066598
May 2010
August 2011
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