Mycophenolate Mofetil (MMF) for Treatment of Chronic Graft-versus-host Disease (GVHD)

A Randomized Study to Evaluate The Efficacy of Mycophenolate Mofetil Added to The Systemic Immunosuppressive Regimen First Used For Treatment of Chronic Graft-Versus-Host Disease

RATIONALE: Mycophenolate mofetil added to immunosuppressive treatment regimens may be effective in treating newly diagnosed chronic graft-versus-host disease caused by stem cell transplantation. It is not yet known whether immunosuppressive treatment regimens are more effective with or without mycophenolate mofetil in treating chronic graft-versus-host disease.

PURPOSE: This randomized phase III trial is studying whether the addition of mycophenolate mofetil improves the efficacy of immunosuppressive treatment regimens in patients with newly diagnosed chronic graft-versus-host disease.

OBJECTIVES:

• Compare the efficacy of immunosuppressive treatment regimens with vs without mycophenolate mofetil in patients with newly diagnosed chronic graft-vs-host disease.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, prospective, multicenter study. Patients are stratified according to organ involvement of chronic graft-versus-host disease (GVHD) (single organ vs multiple organs) and transplant center. Patients are randomized to 1 of 2 treatment arms.

All patients receive usual therapy for chronic GVHD comprising oral prednisone twice daily and oral cyclosporine, oral tacrolimus or oral sirolimus twice daily until 2 weeks after the first evidence of improvement of symptoms of chronic GVHD.

• Arm I: Patients receive oral mycophenolate mofetil twice daily.
• Arm II: Patients receive oral placebo twice daily. In both arms administration of the study drug continues for 3 months after completion of prednisone and cyclosporine, tacrolimus or sirolimus in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then every 3 months.

Patients are followed every 3 months for 3-5 years.

PROJECTED ACCRUAL: A total of 230 patients (115 per treatment arm) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Newly diagnosed chronic-graft-versus host disease (GVHD)
• Systemic immunosuppressive treatment indicated AND no contraindication to treatment with mycophenolate mofetil
• Has undergone prior transplantation with any type of donor, hematopoietic stem cell graft, or conditioning regimen
• No clinical, laboratory, or image-based evidence known to be present at the time of enrollment and indicating a high probability of subsequent recurrent or progressive disease

PATIENT CHARACTERISTICS:

Age

• Any age

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3

Hepatic

• Not specified

Renal

• Not specified

Pulmonary

• No known bronchiolitis obliterans as a manifestation of chronic GVHD

Immunologic

• No fungal infection without radiographic evidence of improvement during continued antifungal therapy
• No cytomegalovirus (CMV) pneumonia without major radiographic evidence of improvement
• No other CMV infection without reduction of antigenemia or viral load during continued antiviral therapy
• No active disseminated varicella zoster viral infection
• No known hypersensitivity or allergy to MMF

Gastrointestinal

• Able to tolerate oral medication
• No lactose-intolerant children who are too young to swallow capsules
• No frank blood from the rectum
• No melena
• No known gastrointestinal ulceration

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

  • Female patients must use 2 forms of contraception 4 weeks prior to, during, and for 6 weeks after completion of study treatment

• Not hospitalized at time of enrollment

• No rare, hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• Not specified

Endocrine therapy

• Prior treatment with prednisone or equivalent allowed provided the dose was ≤ 1.0 mg/kg/day at the time of enrollment
• Concurrent systemic glucocorticoids allowed

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Prior mycophenolate mofetil (MMF) for prevention or treatment of acute GVHD allowed provided MMF was discontinued at least 2 weeks before the diagnosis of chronic GVHD was made
• No prior systemic treatment for chronic GVHD
• No prior treatment for chronic GVHD
• Concurrent antacids allowed provided there is at least a 2-hour interval before and after administration of MMF
• No other concurrent systemic immunosuppressive treatment except cyclosporine, tacrolimus or sirolimus