TBI Dose De-escalation for Fanconi Anemia

Study Treatment: Patients will receive voriconazole (antifungal therapy) by mouth beginning 1
month prior to conditioning therapy, if possible. 1) The subject is to receive total body
irradiation (300 cGy) with thymic shielding; it will be given six days before the stem cells
are given (day -6). 2) Day -5 through Day -2, subjects will receive a chemotherapy regimen of
Fludarabine and Cyclophosphamide via central line (i.e. Hickman or Broviac). Starting Day -3,
patients will receive sirolimus therapy with a taper commencing on day +180 and also
mycophenolate mofetil (MMF) through day +30 or for 7 days after engraftment, whichever day is
later, if no acute graft-versus-host disease (GVHD). 4) If the subject is receiving bone
marrow or "peripheral" stem cells (cells collected from the donor's arm via a cell
separator), on the day of transplantation, the stem cells taken from the donor will be put
into a machine which will separate the lymphocytes (the cells that cause graft-versus-host
disease [GVHD]) from the stem cells. If the subject is receiving an umbilical cord blood, the
lymphocytes will not be removed because the risk of GVHD is not as high. Otherwise all
patients will receive the same treatment. The stem cells are given as an infusion into the
subject's existing catheter over 1-2 hours on day 0.5. On the day after transplant (day +1)
subjects will be given G-CSF to stimulate the growth of the transplanted cells. 6. While
receiving treatment and until the subject's blood counts recover he/she will have daily blood
tests, and several bone marrow biopsies and aspirates. After recovery, subjects will be seen
once a month for a health assessment and blood tests until at least 3 months after the cells
have been infused. Additional blood tests or assessments may be done as medically indicated.

Inclusion Criteria:

Meeting the definition of standard risk or high risk Fanconi anemia as defined in the next
two sections:

- Standard risk patients must be <18 years of age with a diagnosis of Fanconi anemia
with aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high
risk genotype as defined below:

- Aplastic anemia is defined as having at least one of the following when not
receiving growth factors or transfusions:

- platelet count <20 * 10^9/L

- ANC <5 * 10^8/L

- Hemoglobin <8 g/dL

- Myelodysplastic syndrome (MDS) with multilineage dysplasia with or without
chromosomal anomalies

- High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2
mutations)

- High risk patients must have one or more of the following high risk features:

- Advanced MDS (≥ 5% blast) or acute leukemia

- Require additional HSCT for graft failure

- History at any time of systemic fungal or gram negative infection

- Severe renal disease with a creatinine clearance <40 mL/min

- Age > 18 years

- Very high risk patients must have Advanced MDS (≥ 5% blast) or acute leukemia after
initial hematopoietic stem cell transplant (HSCT)

- Patients must have an appropriate source of stem cells. Patients and donors will be
typed for HLA-A, B, C and DRB1 using high resolution molecular typing.

- Adequate major organ function including:

- Cardiac: ejection fraction >45%

- Hepatic: bilirubin, AST or ALT, ALP <5 x normal

- Karnofsky performance status >70% or Lansky >50 (if < 16 years of age)

- Women of child-bearing age must be using adequate birth control and have a negative
pregnancy test.

- Written consent.

Exclusion Criteria:

- Available HLA-genotypically identical related donor in standard risk patients.

- Active central nervous system (CNS) leukemia at time of study enrollment.

- History of squamous cell carcinoma of the head/neck/cervix within previous 2 years.

- Prior radiation therapy that prevents further total body irradiation (TBI).