Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia

PRIMARY OBJECTIVES:

I. Identify doses of total-body irradiation (TBI) that lead to sufficient probability of
donor engraftment (> 5% donor cluster of differentiation [CD]3 chimerism) by day +200.

II. Evaluate the probability of severe acute graft-versus-host disease.

SECONDARY OBJECTIVES:

I. Evaluate the probabilities of overall survival, regimen-related toxicity (RRT), and
recurrent hematopoietic malignancy in those patients with a prior underlying history of such.

II. Examine the degree to which mixed chimerism provides for amelioration of symptoms (i.e.,
infections due to neutropenia, hemorrhage due to thrombocytopenia) associated with bone
marrow failure.

III. Determine if the FA complementation group and % initial mosaicism predict engraftment
and RRT outcomes.

OUTLINE: Patients are assigned to 1 of 4 treatment arms.

NOTE: Patients no longer receive pre-transplant cyclophosphamide as of February 2009.

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

Inclusion Criteria:

- Any patient with FA and bone marrow (BM) failure involving 2 of the following 3
lineages: granulocyte count < 0.5 x 10^9/L, platelet count < 20 x 10^9/L, or
hemoglobin < 8 g/dL

- Any patient with FA who requires red blood cell or platelet transfusions because of
marrow failure

- Any patient with FA who has a life-threatening BM failure involving a single
hematopoietic lineage

- Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic
malignancy (acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) in
morphological remission (defined as absence of circulating blasts and bone marrow
blasts < 5% as assessed by morphology); Note that hematopoietic recovery is not
required for remission status

- Patients must have a negative cytotoxic cross match with donor

- DONOR: Related, human leukocyte antigen (HLA)-haploidentical donors must be identical
for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1
loci of the unshared haplotype

- DONOR: Unrelated, HLA-matched donors must be matched at HLA-A, B, C, DRB1 and DQB1 by
deoxyribonucleic acid (DNA) typing at the highest resolution routinely available at
the time of donor selection; a single allele mismatch at HLA-A, B, or C is allowed OR
a single DQB1 mismatch is allowed

- DONOR: Bone marrow will be the only allowed hematopoietic stem cell source

- DONOR: Haploidentical donor selection will be based on standard institutional
criteria, otherwise no specific prioritization will be made amongst the suitable
available donors

Exclusion Criteria:

- Patients having available HLA-matched related donors

- Significant organ dysfunction that would prevent compliance with conditioning,
graft-versus-host disease (GVHD) prophylaxis, or would severely limit the probability
of survival, such as liver disease/failure (active hepatitis, moderate to severe
portal fibrosis/cirrhosis confirmed by biopsy or uncorrectable hepatic synthetic
dysfunction), lung disease, or cardiac disease (ejection fraction < 35%, or if unable
to obtain ejection fraction, shortening fraction of < 26%; if shortening is < 26% a
cardiology consult is required with principal investigator [PI] having final approval
of eligibility)

- Human immunodeficiency virus (HIV) seropositive patients

- Fertile females who are unwilling to use contraceptive techniques during and for the
twelve months following treatment, as well as females who are pregnant or actively
breast feeding

- Fertile males who are unwilling to use contraceptive techniques during and for the
twelve months following treatment

- AML/MDS in morphological relapse, defined as having circulating blasts or bone marrow
blasts >= 5% as assessed by morphology

- Active infectious disease concerns

- Karnofsky performance score < 50 or Lansky performance score < 40

- DONOR: Donors found to have Fanconi anemia based on chromosomal breakage analysis

- DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1
x 10^8 nucleated cells/kg recipient ideal body weight [IBW]) or who are unwilling to
be bone marrow donors

- DONOR: HIV-positive donors

- DONOR: Donors who are cross-match positive with recipient

- DONOR: Recipient homozygous at mismatched locus; if the recipient is homozygous at
HLA-A, B, or C and the donor is mismatched at that locus, the donor should be avoided;
exceptions must be discussed with the PI