Fludarabine Based RIC for Bone Marrow Failure Syndromes

Eligibility Criteria

• 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.
• * 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 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)
• * 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