Sirolimus, Tacrolimus, and Methotrexate in Preventing Acute Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplantation

A Phase I/II Study of Sirolimus in Addition to Tacrolimus and Methotrexate for the Prevention of Acute-Graft-Versus-Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation From Unrelated Donors

RATIONALE: Sirolimus, tacrolimus, and methotrexate may be effective in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation.

PURPOSE: This phase I/II trial is studying the side effects of sirolimus when given together with tacrolimus and methotrexate and to see how well they work in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation for hematologic cancer.

OBJECTIVES:

Primary

• Determine the safety and efficacy of sirolimus when administered with tacrolimus and methotrexate for the prevention of acute graft-versus-host disease (GVHD) in patients with hematological malignancies undergoing hematopoietic stem cell transplantation from unrelated donors.

Secondary

• Determine the absorption and pharmacokinetics of sirolimus in patients treated with this regimen.
• Correlate sirolimus blood concentration with prevention of GVHD or toxicity in patients treated with this regimen.
• Determine the severity of post-transplantation mucositis in patients treated with this regimen.

OUTLINE: This is a nonrandomized, open-label, pilot study.

Patients receive oral sirolimus once daily on days -3 to 175 and tacrolimus IV continuously beginning on day -3 and continuing until the patient is able to tolerate food and then orally twice daily until day 175. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Treatment continues in the absence of acute graft-vs-host disease or unacceptable toxicity.

Patients are followed for 5 years.

PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Diagnosis of hematological malignancy

  • No chronic phase chronic myelogenous leukemia, de novo acute leukemia in first remission, or myelodysplastic syndromes with refractory anemia

• Scheduled for hematopoietic stem cell transplantation from unrelated donors

• Currently receiving conditioning regimen comprising cyclosporine and total body radiotherapy (1,200 to 1,350 cGy) or busulfan and cyclosporine

• Donor must be typed to the highest level of resolution

  • One single non-serologic disparity for A, B, or C alleles allowed provided the disparity is within the third or fourth digit of the allele
  • No mismatch at DRB1 or DQB1

PATIENT CHARACTERISTICS:

Age

• Per primary treatment protocol

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• SGOT and SGPT ≤ 2.0 times upper limit of normal
• Bilirubin normal
• Hepatitis B and C virus negative

Renal

• Creatinine clearance ≥ 70 mL/min

Cardiovascular

• No cardiac insufficiency requiring treatment
• No coronary artery disease

Pulmonary

• No acute pulmonary infection by chest x-ray
• No severe hypoxemia with pO_2 < 70 mm Hg AND DLCO < 70% of predicted
• No mild hypoxemia with pO_2 < 80 mm Hg AND DLCO < 60% of predicted

Other

• Not pregnant or nursing
• Negative pregnancy test
• HIV negative
• No active systemic infection
• No known hypersensitivity to macrolide antibiotics (e.g., erythromycin, azithromycin, or clarithromycin)
• No prior intolerance or unresponsiveness to sirolimus

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No concurrent T-cell depleted transplantations

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

Other

• No concurrent grapefruit juice
• No concurrent voriconazole