Rituximab for the Primary Treatment of Denovo Extensive Chronic Graft Versus Host Disease (GVHD)

Phase 2

Completed

Conditions: Chronic Graft-versus-host Disease

Interventions: Drug: Rituximab

Registration Number: NCT01161628

Lead Sponsor: Northside Hospital, Inc.

Brief 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

First episode of extensive chronic GvHD, without residual or concurrent acute GvHD.
Age 18 - 75
Any primary diagnosis requiring treatment by allogeneic HSCT
Recipient of an allogeneic stem cell transplant (bone marrow, peripheral blood stem cell, or cord blood) from a related or unrelated donor, minimum 80 days ago
Conditioning regimen: Myeloablative or non-myeloablative
Patient gives written informed consent

Exclusion Criteria

Creatinine > 2.0 mg/dl
Uncontrolled, active infection
Recurrent or progressive malignancy
Anticipated life expectancy of less than 1 year
Pregnant or breast feeding
Contraindications to administration of the study intervention or known inability of the patient to tolerate the study intervention
Patients with perceived fixed, irreversible defects (pulmonary involvement, contractures, etc.) which would not be expected to improve with the study intervention
Residual or concurrent acute GVHD

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Rituxan	Rituximab	All patients receive 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.

Primary Outcome Measures

Name	Time	Method
Rate of Complete Response of cGVHD to Treatment.	2 years
Rate of Overall Response of cGVHD to Treatment	2 years
Rate of Partial Response of cGVHD to Treatment	2 years

Secondary Outcome Measures

Name	Time	Method
Requirement for Systemic Corticosteroid Use	2 years
Time to Immunosuppression Withdrawal	2 years
Incidence of Overall Survival	2 years
Duration of Systemic Corticosteroid Use	2 years
Incidence of Disease-free Survival	2 years
Incidence of Non-relapse Mortality	2 years