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

Inclusion Criteria:

• Acquired and Inherited Bone Marrow Failure Conditions Associated with Trilinear BoneMarrow Failure

• Acquired Aplastic Anemia

1. Must meet criteria for severe or very severe aplastic anemia (AA), definedby: i. Bone marrow biopsy demonstrating cellularity of <25% overall or bonemarrow biopsy that is overall hypocellular for age by pathology reportwith reductions in any two hematopoietic lineages (myeloid, erythroid, ormegakaryocyte) ii. In addition, 2 of the following must be met:
2. absolute neutrophil count (ANC) < 500/µL (severe) or < 200/µL (verysevere). Current ANC or last ANC prior to start of Granulocyte-colonystimulating factor (G-CSF) may be used.
3. platelets < 30,000/µL or transfusion dependence
4. absolute reticulocyte count < 40,000/µL iii. Negative evaluation for inherited bone marrow failure conditions (seebelow) iv. Must not have accompanying diagnosis of myelodysplastic syndrome
5. Patients meeting other eligibility criteria may receive study therapy asthe initial treatment approach provided an eligible unrelated ormismatched related ("haplo") donor is available
6. Patients who have received prior immune suppression therapy will beeligible if they have refractory or relapsed disease defined as pertreating clinician's judgement, at least 12 weeks after initiation ofimmune suppression therapy. Relapsed patients who previously methematologic criteria for severe aplastic anemia do not have to meet thesehematologic criteria for severe aplastic anemia at time of relapse to beeligible for transplant.

• Paroxysmal Nocturnal Hemoglobinuria

1. Patients must have testing (eg. Flow Cytometry demonstrating cells withabsent cluster of differentiation 55 (CD55) or cluster of differentiation 59 (CD59) expression demonstrating a PNH clone in greater than 10% ofperipheral blood red blood cells and/or granulocytes, along with clinicalor laboratory evidence of intravascular hemolysis, such as: i. Elevated Lactate dehydrogenase (LDH) ii. Low to absent serum haptoglobin iii. Hemoglobinuria iv. Reticulocytosis v. Studies demonstrating aberrant complement activation
2. Patients who have small paroxysmal nocturnal hemoglobinuria (PNH) clones,no evidence of hemolysis, and meet criteria for severe or very severe AAas defined above, will be classified as acquired AA for treatmentstratification.

• Fanconi Anemia

1. To be eligible, patients must meet the following criteria: i. Must have evidence of BM failure, defined as a bone marrow biopsydemonstrating cellularity of <25% in addition to peripheral bloodcytopenias ii. Must have chromosomal breakage (stress) testing performeddemonstrating increased sensitivity to DNA damage caused by mitomycin C (MMC) or diepoxybutane (DEB) iii. Specific testing to define the subtype of Fanconi Anemia throughgenetic sequencing for causative mutations or complementation groupstudies is strongly recommended, though not required.

• Dyskeratosis Congenita and related telomere disorders

1. To be eligible, patients must meet the following criteria: i. Must have evidence of BM failure, defined as a bone marrow biopsydemonstrating cellularity of <25% in addition to peripheral bloodcytopenias ii. Must have lymphocyte telomere length analysis performed at a ClinicalLaboratory Improvement Amendments (CLIA)-certified facility, demonstratingtelomeres <1%ile for age iii. Specific gene sequencing testing to define the causative geneticmutation is strongly recommended, though not required.

• Shwachman-Diamond Syndrome

1. To be eligible, patients must meet the following criteria: i. Must have genetic testing confirming a mutation in theShwachman-Bodian-Diamond syndrome (SBDS) gene, and/or classic clinicalfeatures of Shwachman-Diamond Syndrome, including pancreaticinsufficiency, musculoskeletal anomalies, and endocrinopathies ii. Must have developed trilineage BM failure, including BM cellularity < 25%.
2. Patients meeting the above criteria for Shwachman-Diamond syndrome will beeligible 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 LineageFailure

• Severe Congenital Neutropenia

1. To be eligible, patients must meet the following criteria: i. Have a baseline ANC < 500/µL prior to G-CSF therapy

ii. Require chronic G-CSF therapy greater than 3 doses per week in order to maintain an ANC > 1000/µL

iii. Have genetic testing demonstrating mutation(s) in a gene known to cause severe congenital neutropenia and/or have negative testing for autoimmune causes of neutropenia or BM biopsy demonstrating myeloid lineage arrest at neutrophil precursor stage.

iv. History of severe bacterial or fungal infection associated with neutropenia, including, but not limited to, pneumonia, osteomyelitis, mastoiditis, or bacteremia. If no infection history, must otherwise have evidence of toxicity due to chronic G-CSF therapy, including osteopenia, splenomegaly or isolated cytogenetic abnormalities.

• Isolated disorders of erythropoiesis:

1. Includes, but not limited to: i. Diamond-Blackfan Anemia (DBA) ii. CongenitalDyserythropoietic Anemia (CDA) iii. Congenital Sideroblastic Anemia (CSA) 2.Eligibility criteria include: i. Chronic red blood cell (RBC) TransfusionDependence, with minimum frequency of every 8 weeks ii. BM aspirate and biopsydemonstrating selective erythroid hypoplasia or dyserythropoiesis iii. Forpatients with DBA, must have failed at least one therapeutic trial withcorticosteroids iv. Acquired viral and autoimmune causes of hypo-productiveanemia have been excluded v. Specific genetic testing attempting to define thecausative mutation is recommended but not required o Congenital Thrombocytopenia Syndromes

2. Includes, but is not limited to, patients with Congenital AmegakaryocyticThrombocytopenia caused by mutations in the MPL gene 2. Eligibility criteriainclude: i. Platelet transfusion dependence with a minimum transfusionfrequency of every 8 weeks ii. Infectious, autoimmune, and other causes ofsecondary thrombocytopenia have been excluded iii. Genetic sequencing of theMPL gene is required iv. Additional genetic testing for causes of familialthrombocytopenia 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 tocomply with pulmonary function testing (PFTs) or no baseline oxygen requirementfor younger patients.

• Lansky or Karnofsky performance >= 60

• Infectious disease criteria

• No active, untreated infections

• Patients with likely bacterial infections must be receiving appropriateantibacterial therapy and demonstrating therapy response

• Patients with likely fungal infections must have had at least 2 weeks ofappropriate anti-fungal antibiotics and be asymptomatic.

• Patients with symptoms consistent with active viral infection will be deferreduntil viral symptoms resolve. Patients with evidence of cytomegalovirus (CMV),Epstein-Barr virus (EBV) or other known viremia must receive appropriatetherapy to clear viremia prior to initiating study therapy.

• Signed consent by parent/guardian or able to give consent if >= 18 years

Exclusion Criteria:

• Patients who do not meet disease, organ or infectious criteria.

• 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 no suitable closely Human leukocyte antigen (HLA)-matched unrelated orrelated haploidentical matched donor available. Patients with suitable fully matchedrelated donor are also not eligible.

• Pregnant females. All females of childbearing potential must have negative pregnancytest.

Donor selection and eligibility:

• Donor selection will comply with 21 Code of Federal Regulations (CFR 1271) of the U.S. Food and Drug Administration's Code of Federal Regulations

Donor testing:

• 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 donoreligibility, including donor screening and testing for relevant communicable diseaseagents and diseases. The donor collection program is FACT accredited.

• For partially matched related donors, if subject has genetically confirmed iBMFsyndrome, related donor must be evaluated for this disorder and testing must benegative

• Infectious disease testing of donor will be per current Blood and Marrow TransplantProgram Standards of Practice as per 21 CFR Part 1271. Donor medical records andhistory are reviewed to confirm that the donor is free of infectious risk factorsand meets donor eligibility criteria as defined by 21 CFR 127.

Donor matching

• 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 beallowed

• 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.