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:

1. To assess the toxicity of a prolonged administration of maraviroc in patients undergoing
RIC SCT.

2. 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.

3. To assess the effect of treatment with maraviroc on immune recovery, engraftment and
donor T-cell chimerism in peripheral blood and in target organs.

4. 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.