Phase II Maraviroc for GVHD Prevention

Detailed Description:

PRIMARY OBJECTIVES:

To estimate the cumulative incidence of grade 2-4 acute GVHD by day 180 with the addition of maraviroc to a standard prophylaxis regimen in patients with hematologic malignancies undergoing reduced intensity allogeneic stem-cell transplantation (RIC SCT) from unrelated donors.

SECONDARY OBJECTIVES:

• To assess the toxicity of a prolonged administration of maraviroc in patients undergoing RIC SCT.
• To estimate the rates of severe (grade 3-4) acute GVHD by day 100 and 180, grade 2-4 acute GVHD by day 100, organ-specific acute GVHD, chronic GVHD, relapse, infections, non-relapse mortality, use of immunosuppressive therapies and 1-year survival in patients treated with maraviroc after RIC SCT.
• To assess the effect of treatment with maraviroc on immune recovery, engraftment and donor T-cell chimerism in peripheral blood and in target organs.
• To assess the effect of donor and recipient CCR5 genotype on the incidence of acute GVHD in patients receiving maraviroc as part of a GVHD prophylaxis regimen.

OUTLINE: Patients receive a standard conditioning regimen with fludarabine and busulfan followed by a peripheral blood stem cell infusion from an unrelated donor, standard GVHD prophylaxis and standard antiviral and antifungal prophylaxis. In addition, all patients receive maraviroc from day -3 to d+ 90.

Patients are followed for 1 year after the stem-cell infusion.

Inclusion criteria

• Patients ≥18 years of age with a hematologic malignancy other than aplastic anemia or primary myelofibrosis, scheduled to undergo RIC allogeneic SCT with a peripheral blood stem cell graft from an unrelated donor, using Flu/Bu conditioning and Tac/MTX GVHD prophylaxis. The following diagnoses are included:

• Acute leukemia - AML, ALL or acute biphenotypic leukemia. Patients will have documentation of complete remission within 6 weeks prior to their transplant. Complete remission is defined as <5% blasts on a bone marrow biopsy and absence of any known extramedullary disease.
• Chronic myelogenous leukemia in any stage, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
• Myelodysplastic syndrome of any subtype, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
• Myeloproliferative disorders other than primary myelofibrosis.
• Lymphoma - All types of lymphoma are eligible.
• CLL and PLL.
• Patients who meet institutional eligibility criteria for allogeneic SCT:

• Renal function: Serum creatinine ≤2.
• Hepatic function: Baseline direct bilirubin, ALT or AST lower than three times the upper limit of normal.
• Pulmonary disease: FVC or FEV1 ≥ 40% predicted.
• Cardiac ejection fraction ≥ 40%.
• Availability of an unrelated donor, identified and screened by the NMDP. The donor will have at least 7/8 HLA-A, -B, -C and -DRB1 matching by high resolution molecular typing and will meet NMDP eligibility criteria to serve as a peripheral blood stem-cell donor.
• Karnofsky score ≥ 70% at the time of screening.
• Capacity to understand and sign the study informed consent form.
• Negative pregnancy test. Women of childbearing potential (not having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of > 1 year) must agree to use documented reliable method(s) of contraception. Men should agree to use condoms during the study period.

• Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.

Exclusion criteria

• Patients with aplastic anemia or primary myelofibrosis. Patients with marrow fibrosis secondary to MDS, AML or a myeloproliferative disorder other than primary myelofibrosis are eligible.
• Patients who are not expected to be available for follow-up in our institution for at least 180 days after the transplant.
• Prior allogeneic SCT.
• Uncontrolled bacterial, viral or fungal infections.
• Patients who receive maraviroc for the treatment of HIV infection.
• Patients receiving other investigational drugs for GVHD.
• Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.
• Patients with prior malignancies are excluded unless treated with curative intent and known to be free of disease for at least 2 years.