Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

PRIMARY OBJECTIVES:

I. To determine whether donor chimerism can be achieved in patients with Fanconi anemia
receiving marrow or peripheral blood stem cell (PBSC) grafts from unrelated donors following
low dose total body irradiation (TBI), fludarabine (fludarabine phosphate), mycophenolate
mofetil, and cyclosporine.

II. To determine the lowest dose of TBI necessary to achieve donor chimerism in at least 80%
of patients.

III. To determine the incidence of severe regimen-related toxicity.

SECONDARY OBJECTIVES:

I. To determine the survival of Fanconi anemia patients transplanted with unrelated donor
marrow or PBSC grafts after conditioning with a non-myeloablative regimen.

II. To determine the incidence and severity of graft-vs-host disease (GVHD) incurred with
unrelated bone marrow or PBSC grafts transplant patients with Fanconi anemia.

III. To determine if mixed chimerism results in amelioration of symptoms associated with
bone marrow failure in patients with Fanconi anemia.

OUTLINE:

NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously
(IV) over 30 minutes on days -4 to -2, cyclosporine IV every 8-12 hours on days -3 to 0, and
undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic bone marrow or PBSC transplantation on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 8-12 hours on days
1-100 with taper to day 177, and mycophenolate mofetil PO or IV every 8 hours on days 0-40
with taper to day 96.

After completion of study treatment, patients are followed up at 6 months and annually
thereafter.

Inclusion Criteria:

- Any patient with marrow failure and increased chromosome fragility as determined in
the diepoxybutane (DEB) or mitomycin C test

- Any patient with Fanconi anemia (FA) with marrow failure meeting the following
criteria:

- Granulocyte count < 0.2 x 10^9/L

- Platelet count < 20 x 10^9/L

- Hemoglobin < 8 g/dl

- Corrected reticulocyte count <1%

- Any patient with FA as determined by DEB fragility, who has life-threatening marrow
failure involving a single hematopoietic lineage

- Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic
malignancy (myelodysplastic syndromes [MDS] or acute myeloid leukemia [AML]) in
remission

- DONOR: Unrelated Donors who are prospectively: Matched for human lymphocyte antigen
(HLA)-DRB1 and DQB1 alleles (must be defined by high resolution typing); only a
single allele disparity will be allowed for HLA -A, B, or C as defined by high
resolution typing

- DONOR: HLA typing will be performed at the highest level of resolution available at
the time of transplant

Exclusion Criteria:

- Evidence for hematopoietic malignancy in relapse

- Heart or lung disease that would prevent compliance with conditioning and GvHD
regimen or would severely limit the probability of survival

- Human immunodeficiency virus (HIV) seropositive patients

- Females who are pregnant or breastfeeding, or unwilling to use contraceptive
techniques during and for the 12 months following treatment

- DONOR: Donors who by DEB testing are found to have FA

- DONOR: Donors who test positive in the lymphocytotoxic crossmatch assay

- DONOR: Donors who are HIV positive

- DONOR: Donors who for other medical or psychological reasons are not suitable as
donors