Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

OBJECTIVES:

Primary

- Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients
with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+
T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this
to relevant historical experience.

- Estimate the probability of graft failure in these patients.

Secondary

- Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these
patients.

- Estimate the probability of transplant-related mortality by day 100 in these patients.

- Estimate the probability of relapse in these patients.

- Estimate the probability and severity of chronic GVHD in these patients.

OUTLINE: This is a multicenter study.

- Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily
for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days
(Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to
-2.)

- Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell
(PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0.

- Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort
1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly
reduced (compared to historical controls), subsequent patients are enrolled in cohort 2.

- Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily
beginning on day -1 and continuing until day 50, followed by a standard taper in
the absence of grade II-IV acute GVHD.

- Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily
beginning on day -1 and continuing until day 30, followed by a rapid taper in the
absence of grade II-IV acute GVHD.

Patients are followed actively for at least 1 year post transplant.

DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following:

- Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or
subsequent remission

- ALL or AML in relapse or primary refractory ALL or AML with a circulating blast
count ≤ 10,000/mm^3

- Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has
received induction chemotherapy within the past 60 days

- Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT)

- No CNS involvement refractory to intrathecal chemotherapy and/or standard
cranial-spinal radiotherapy

PATIENT CHARACTERISTICS:

- Age 14-55

- Creatinine < 1.5 mg/dL

- Cardiac ejection fraction > 45%

- DLCO corrected > 60% of predicted

- Total bilirubin < 2 times upper limit of normal (ULN) (unless attributed to Gilbert
syndrome)

- AST and ALT < 2 times ULN

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for 12 months after
transplantation

- HIV negative

- No co-existing disease (other than leukemia or RAEB) that would limit life expectancy
to < 3 months

- No uncontrolled infection that, in the opinion of the consulting infectious disease
physician, would contraindicate myeloablative HSCT

- No other medical condition that would contraindicate HSCT

- No known hypersensitivity to tacrolimus

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior HSCT

- No concurrent participation in other experimental studies for the prevention of
graft-vs-host disease

DONOR CHARACTERISTICS:

- Genotypic or phenotypic HLA-identical related donor

- Able to donate peripheral blood stem cells

- Age > 14 years

- Applicable to male patients only: No female donors who have previously given birth to
a male child or have had a pregnancy beyond the first trimester miscarriage or
termination of pregnancy or nursing

- No donors who have received blood transfusions

- No CD45 Mutation with aberrant CD45RA isoform expression