Fludarabine Based RIC for Bone Marrow Failure Syndromes

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 weeksfrom last dose of G-CSF), in addition to 2 of the following: absoluteneutrophil count (ANC) <500/µL, platelets < 20,000/µL and absolutereticulocytes <40,000/µL

• Negative evaluation for inherited bone marrow failure conditions andnegative evaluation for dysplasia or cytogenetic abnormalities associatedwith myelodysplastic syndromes

• Patients with concurrent paroxysmal nocturnal hemoglobinuria (PNH) clonesare eligible, as long as they meet criteria for severe or very severeaplastic 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/oran absolute neutrophil count <500/µL. These disorders include, but are notlimited 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 <5xnormal

• 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 FederalRegulations

• 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 disorderand testing must be negative

• Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) proceduresapply for determining donor eligibility, including donor screening and testing forrelevant 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 bycombination 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