Rituximab for GVHD (Rituximab GVHD)
This is a prospective, open-label pilot study in which 4 doses of Rituximab are administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT). The study is designed to determine the overall survival at 180 days after treatment with rituximab, and evaluates the safety and clinical response to rituximab in this study population. Study entry: Patients must enter study on or before day +100 posttransplant.
Graft vs Host Disease
Alogenic Hematopoietic Transplant
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||CHIMERIC MONOCLONAL CD-20 ANTIBODY (RITUXIMAB) FOR STEROID REFRACTORY ACUTE GRAFT VERSUS HOST DISEASE (SR-AGVHD): A PILOT STUDY|
- Complete response rate at 4 and 8 weeks in patients with SR-GVHD treated with Rituximab. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
- Survival at day 180 after txt with rituximab. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
- Partial response rates at 4 weeks and 8 weeks, mixed response rate, and disease progression in patients treated with these regimens. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
- Treatment failure rate at 2 weeks (no response, progression, or mortality). [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
- Safety of rituximab in SR-GVHD [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- Time to aGVHD improvement. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- Incidence of GVHD flares requiring further therapeutic intervention within 90 days of therapy. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- Incidence of discontinuation of immune suppression without flare by days 90, 180, and 270 post therapy. [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
- Incidence of chronic GVHD by 9 months (Day 270) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
- Measurement of total dose of steroids. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Overall survival at 6, 9 and 12-month post initiation of therapy. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Incidence of systemic infections within 3 months of initiation of therapy. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- Relapse of primary disease. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- - Changes in the Karnofsky/Lansky performance status. - Incidence of Epstein-Barr virus-associated lymphoma - Recovery of T-and B-cells. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2007|
Four Rituximab doses administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT)
Rituximab 375 mg/m^2 is given weekly X 4. For patients with a partial response, an additional 4 doses will be permitted as needed (after 4 weeks from the last dose).
Diagnosis of grade II to IV aGVHD will be confirmed, whenever possible, by a biopsy taken from at least one of the following three sites: skin, gut, or liver.
Acute graft-versus-host disease (aGVHD), one of the most important complications of allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality. Grades II to IV aGVHD occur in 30% to 50% of matched related donor recipients and 50% to 70% of unrelated donor recipients. Standard first-line treatment consists of methylprednisolone at a dose of 2 mg/kg/d or equivalent that produces response rates of 63% to 95% for grade II, 17% to 39% for grade III, and 0% to 6% for grade IV aGVHD. In aggregate, approximately 40% to 50% of patients with acute GVHD experience a complete or partial response with primary therapy, whereas 20% to 60% require salvage treatments. The 1994 consensus conference on acute GVHD grading reported 100-day survival rates of 78% to 90% with grade I, 66% to 92% with grade II, 29% to 62% for grade III, and 23% to 25% for grade IV. The higher mortality rates were directly attributable to acute GVHD or to the subsequent immunosuppression from high-dose corticosteroids and other medications required for treatment of GVHD.
Despite several studies seeking to improve first-line therapy for acute GVHD, standard care remains moderate-dose corticosteroids. Higher initial doses of corticosteroids, a more prolonged steroid tapering course, and addition of murine or equine anti-T-cell antibodies to standard GVHD therapy all failed to improve response rates. Acute GVHD therefore remains an unfavorable complication of transplantation that is difficult to manage. Various immunosuppressants including, Anti-thimocyte globulin (ATG), Denileukin Diftitox, Mycophenolate mofetil, Pentostatin, Infliximab, Rapamycin, Inolimomab and Daclizumab have been tried with variable success (table-1 in full protocol); there remains no consensus on the second-line treatment of aGVHD.
Acute graft-versus-host-disease (aGVHD) is mediated by donor T-cells. The preventative and therapeutic strategies described above have therefore focused on quantitative reduction in T cells or reduction of their function through immune-modulation. The role of B-lymphocytes in the pathogenesis of GHVD is unclear. Recent reports of successful use of rituximab in cGVHD support the hypothesis that a coordinated B and T cell response is instrumental in cGVHD. The significance of B-cells in pathogenesis of aGVHD is unknown.
Steroid Refractory Acute Graft-Versus-Host-Disease (SR-aGVHD) Initial treatment for aGVHD routinely consists of intensifying the dose of corticosteroids. This condition is called steroid-resistant (SR) aGVHD and requires secondary intervention.
Rituximab is a human/murine chimeric monoclonal anti CD-20 antibody that is extensively used in patients with B-cell non-Hodgkin's lymphoma, or with autoimmune disease. The incidental observation of improvement in aGVHD following rituximab infusion for transplant-associated thrombotic thrombocytopenic purpura (TA-TTP) and subsequent complete resolution of multi-agent refractory aGVHD in two patients forms the basis of this proposed pilot study. Table-2 (in full protocol) describes the patients and their responses to rituximab at our own institution.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00578591
|United States, Texas|
|Texas Children's Hospital|
|Houston, Texas, United States, 77030|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Rammurti Kamble, MD||Baylor College of Medicine/TCH/Methodist|