Fludarabine Based RIC for Bone Marrow Failure Syndromes

Acquired AA patients will receive the experimental regimen of fludarabine with dose-reduced
cyclophosphamide, with results in this prospective single arm experimental group evaluated in
the context of our institutional historical experience using HD Cy regimens as well as
published outcomes using both fludarabine and high-dose cyclophosphamide-based regimens for
MRD-BMT in aplastic anemia. iBMF syndrome patients will receive one of two
fludarabine-containing regimens based on disease characteristics, and our outcomes will be
compared to previously published data using a variety of regimens. Graft versus host disease
(GvHD) prophylaxis will consist of cyclosporine/tacrolimus alone for patients with acquired
AA or cyclosporine/tacrolimus plus mycophenolate for patients with iBMF syndromes. For both
acquired AA and iBMF syndrome patients, donor chimerism will be assessed at scheduled
intervals following BMT and will be used to define patients with full donor or mixed
chimerism for comparisons of survival, graft failure, cytogenetic, GvHD, and immune
reconstitution outcomes.

Patients 0-22 years with acquired aplastic anemia or a diagnosed inherited bone marrow
failure syndrome, and a fully Human leukocyte antigen (HLA)-matched (10/10) related donor.

Inclusion Criteria:

Patient:

1. Ages 0-22 years at time of enrollment

2. Diseases:

- Patients with severe or very severe acquired AA, defined by:

- Bone marrow biopsy demonstrating cellularity of <25% (at least 2 weeks from
last dose of G-CSF), in addition to 2 of the following: absolute neutrophil
count (ANC) <500/µL, platelets < 20,000/µL and absolute reticulocytes
<40,000/µL

- Negative evaluation for inherited bone marrow failure conditions and
negative evaluation for dysplasia or cytogenetic abnormalities associated
with myelodysplastic syndromes

- Patients with concurrent paroxysmal nocturnal hemoglobinuria (PNH) clones
are eligible, as long as they meet criteria for severe or very severe
aplastic anemia as defined above

- Patients with clinically diagnosed and/or genetically proven iBMF syndromes,
resulting in chronic red blood cell or platelet-transfusion dependence and/or an
absolute neutrophil count <500/µL. These disorders include, but are not limited
to:

- Fanconi Anemia

- Dyskeratosis Congenita

- Severe Congenital Neutropenia

- Diamond-Blackfan Anemia

- Congenital Dyserythropoietic/Sideroblastic Anemias

- Congenital Amegakaryocytic Thrombocytopenia

- Shwachman-Diamond Syndrome

3. Lansky or Karnofsky performance >60

4. HLA matched related donor available.

5. No active untreated infection

6. Females of childbearing potential must have negative pregnancy test.

Organ Function:

- Serum creatinine <1.5xupper limit of normal for age Hepatic: Transaminases <5x normal

- Cardiac shortening fraction >27%

- Bilirubin <2.5x normal (unless elevation due to Gilberts disease).

Donor Selection Criteria:

- Donor selection will comply with U.S. Food and Drug Administration's Code of Federal
Regulations

- Fully HLA-matched related donor.

- Donor must be at least 6 months of age

- Donor suitable for bone marrow collection and meets eligibility for donation,
including fulfilling infectious disease criteria as per SOP, including HIV, Hepatitis
B, Hepatitis C Polymerase chain reaction (PCR) negative.

- If subject has confirmed iBMF syndrome, donor must be evaluated for this disorder and
testing must be negative

- Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) procedures
apply for determining donor eligibility, including donor screening and testing for
relevant communicable disease agents and diseases.

- Donor evaluation and collection procedure as per CHOP Standard Operating Procedures
(SOP)

Exclusion Criteria:

- Uncontrolled bacterial, viral or fungal infections

- HLA matched related donor unable to donate bone marrow.

- No eligible fully HLA-matched related donor

- Pregnant females

- Patients with a clinical diagnosis of Myelodysplastic syndrome (MDS) defined by
combination of bone marrow dysplasia and classic cytogenetic lesion (Monosomy 7,
Trisomy 8 eg.), with or without excess blasts.

- Patients with PNH without underlying bone marrow aplasia