Unrelated And Partially Matched Related Donor PSCT w/ T Cell Receptor (TCR) αβ Depletion for Patients With BMF

Eligibility Criteria

• * Acquired and Inherited Bone Marrow Failure Conditions Associated with Trilinear Bone Marrow Failure
• * Acquired Aplastic Anemia
• 1. Must meet criteria for severe or very severe aplastic anemia (AA), defined by:
• 1. absolute neutrophil count (ANC) \< 500/µL (severe) or \< 200/µL (very severe). Current ANC or last ANC prior to start of Granulocyte-colony stimulating factor (G-CSF) may be used.
• 2. platelets \< 30,000/µL or transfusion dependence
• 3. absolute reticulocyte count \< 40,000/µL
• 2. Patients meeting other eligibility criteria may receive study therapy as the initial treatment approach provided an eligible unrelated or mismatched related ("haplo") donor is available
• 3. Patients who have received prior immune suppression therapy will be eligible if they have refractory or relapsed disease defined as per treating clinician's judgement, at least 12 weeks after initiation of immune suppression therapy. Relapsed patients who previously met hematologic criteria for severe aplastic anemia do not have to meet these hematologic criteria for severe aplastic anemia at time of relapse to be eligible for transplant.
• * Paroxysmal Nocturnal Hemoglobinuria
• 1. Patients must have testing (eg. Flow Cytometry demonstrating cells with absent cluster of differentiation 55 (CD55) or cluster of differentiation 59 (CD59) expression demonstrating a PNH clone in greater than 10% of peripheral blood red blood cells and/or granulocytes, along with clinical or laboratory evidence of intravascular hemolysis, such as:
• 2. Patients who have small paroxysmal nocturnal hemoglobinuria (PNH) clones, no evidence of hemolysis, and meet criteria for severe or very severe AA as defined above, will be classified as acquired AA for treatment stratification.
• * Fanconi Anemia
• 1. To be eligible, patients must meet the following criteria:
• * Dyskeratosis Congenita and related telomere disorders
• 1. To be eligible, patients must meet the following criteria:
• * Shwachman-Diamond Syndrome
• 1. To be eligible, patients must meet the following criteria:
• 2. Patients meeting the above criteria for Shwachman-Diamond syndrome will be eligible for conditioning regimen #1 with dosing of Total Body Irradiation (TBI) and cyclophosphamide according to the dyskeratosis congenita regimen
• * Inherited Bone Marrow Failure Conditions Associated with Predominant Single Lineage Failure
• * Severe Congenital Neutropenia
• 1. To be eligible, patients must meet the following criteria:
• * Isolated disorders of erythropoiesis:
• 1. Includes, but not limited to: i. Diamond-Blackfan Anemia (DBA) ii. Congenital Dyserythropoietic Anemia (CDA) iii. Congenital Sideroblastic Anemia (CSA) 2. Eligibility criteria include: i. Chronic red blood cell (RBC) Transfusion Dependence, with minimum frequency of every 8 weeks ii. BM aspirate and biopsy demonstrating selective erythroid hypoplasia or dyserythropoiesis iii. For patients with DBA, must have failed at least one therapeutic trial with corticosteroids iv. Acquired viral and autoimmune causes of hypo-productive anemia have been excluded v. Specific genetic testing attempting to define the causative mutation is recommended but not required
• 1. Includes, but is not limited to, patients with Congenital Amegakaryocytic Thrombocytopenia caused by mutations in the MPL gene 2. Eligibility criteria include: i. Platelet transfusion dependence with a minimum transfusion frequency of every 8 weeks ii. Infectious, autoimmune, and other causes of secondary thrombocytopenia have been excluded iii. Genetic sequencing of the MPL gene is required iv. Additional genetic testing for causes of familial thrombocytopenia is recommended but not required
• * Organ function status
• * Renal: Serum creatinine \<1.5x upper limit of normal for age
• * Hepatic: Transaminases \<500 upper limit of normal. Bilirubin \<2.5 mg/dL, (unless elevation due to Gilberts disease or known hemolytic anemia).
• * Cardiac: shortening fraction \>= 27%
• * Pulmonary: Diffusing Capacity (DLCO) \>= 50% predicted in patients old enough to comply with pulmonary function testing (PFTs) or no baseline oxygen requirement for younger patients.
• * Lansky or Karnofsky performance \>= 60
• * Infectious disease criteria
• * No active, untreated infections
• * Patients with likely bacterial infections must be receiving appropriate antibacterial therapy and demonstrating therapy response
• * Patients with likely fungal infections must have had at least 2 weeks of appropriate anti-fungal antibiotics and be asymptomatic.
• * Patients with symptoms consistent with active viral infection will be deferred until viral symptoms resolve. Patients with evidence of cytomegalovirus (CMV), Epstein-Barr virus (EBV) or other known viremia must receive appropriate therapy to clear viremia prior to initiating study therapy.
• * Signed consent by parent/guardian or able to give consent if \>= 18 years
• * Patients who do not meet disease, organ or infectious criteria.
• * 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 no suitable closely Human leukocyte antigen (HLA)-matched unrelated or related haploidentical matched donor available. Patients with suitable fully matched related donor are also not eligible.
• * Pregnant females. All females of childbearing potential must have negative pregnancy test.
• * Unrelated donor meets National Marrow Donor Program criteria for donation
• * For partially matched related donors, Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) standard procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases. The donor collection program is FACT accredited.
• * For partially matched related donors, if subject has genetically confirmed iBMF syndrome, related donor must be evaluated for this disorder and testing must be negative
• * Infectious disease testing of donor will be per current Blood and Marrow Transplant Program Standards of Practice as per 21 CFR Part 1271. Donor medical records and history are reviewed to confirm that the donor is free of infectious risk factors and meets donor eligibility criteria as defined by 21 CFR 127.
• * High resolution HLA typing at HLA-A, -B, -C, DRB1, and DQB1 loci
• * Unrelated donor
• * Donor must be an antigen and allele match at ≥ 8/10 HLA Loci
• * In donor with 2 mismatches, only one mismatch involving HLA-A, -B, or -DRB1 will be allowed
• * Donor and collection center willing to undergo mobilization and apheresis
• * Partially matched related donor
• * Related donor must be ≥ 5/10 but \< 10/10 HLA match
• * Donor must be willing to undergo G-CSF mobilization and stem cell apheresis.