Sirolimus and Mycophenolate Mofetil (MMF) as Graft Versus Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Transplantation

• Donor stem cell engraftment, including donor-host hematopoietic chimerism studies post transplant [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• The rate of renal insufficiency [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• To correlate the serum concentrations of mycophenolate mofetil and its metabolites with acute GVHD incidence [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Incidence of 100 day mortality [ Time Frame: 100 days ] [ Designated as safety issue: No ]
• Incidence of chronic GVHD [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]

• Donor stem cell engraftment, including donor-host hematopoietic chimerism studies post transplant. [ Time Frame: 1 year ]
• The rate of renal insufficiency [ Time Frame: 1 year ]
• To correlate the serum concentrations of mycophenolate mofetil and its metabolites with acute GVHD incidence [ Time Frame: 1 year ]
• Incidence of 100 day mortality [ Time Frame: 100 days ]
• Incidence of chronic GVHD [ Time Frame: 1 year ]
• Overall survival [ Time Frame: 1 year ]

This trial will test the hypothesis that the combination of sirolimus and mycophenolate mofetil will be effective in preventing both acute and chronic GVHD after reduced intensity allogeneic stem cell transplantation.

The combination of tacrolimus and methotrexate is standard therapy for prevention of GVHD, however, our recent experience has demonstrated that the substitution of sirolimus for methotrexate provides superior GVHD control with reduced transplant-related toxicity. One limitation to the use of calcineurin inhibitors in GVHD prevention is the disruption in Treg function and proliferation. Based on our evolving understanding of the role of Treg in the development of chronic GVHD, we propose a GVHD prophylactic regimen that is effective in prevention of acute GVHD, but by virtue of the maintenance of Treg activity may be able to prevent chronic GVHD. We hypothesize that the substitution of mycophenolate mofetil for tacrolimus may provide similar protection against acute GVHD and prevent chronic GVHD while minimizing renal toxicity after transplantation.

Inclusion Criteria:

1. Patients with hematologic malignancies, who are at high risk of complications after conventional myeloablative transplantation
2. Patients must have a 6/6 matched, related donor. Matching at HLA Class II will be based on PCR of sequence specific primers (SSP). Among family member transplants, serologic matching at Class I is sufficient
3. Patient age greater than 18
4. Performance status 0-2
5. Life expectancy of > 100 days without transplantation
6. Written informed consent must be obtained in all cases from the patient

Exclusion Criteria:

1. Pregnancy
2. Prior Allogeneic Stem Cell Transplantation from any donor
3. Evidence of HIV infection or active Hepatitis B or C infection
4. Heart failure uncontrolled by medications
5. Total bilirubin > 2.0 mg/dl that is due to hepatocellular dysfunction
6. AST > 90
7. Cholesterol > 300 mg/dl or Triglycerides > 400 mg/dl while adequately treated
8. Uncontrolled bacterial, viral or fungal infection
9. Requirement for voriconazole at the time of hospital admission

• Wyeth is now a wholly owned subsidiary of Pfizer
• PDL BioPharma, Inc.