Unrelated and Partially Matched Related Donor Peripheral Blood Stem Cell Transplant with TCR alpha/beta+ T Cell and B Cell Depletion for the Treatment of Patients with Acquired or Inherited Bone Marrow Failure

Inclusion Criteria

• All ethnic backgrounds will be eligible
• Acquired and inherited bone marrow failure conditions associated with trilinear bone marrow failure
• Acquired aplastic anemia * Must meet criteria for severe or very severe aplastic anemia (AA), defined by: ** Bone marrow biopsy demonstrating cellularity of < 25% ** In addition, 2 of the following must be met: *** Absolute neutrophil count (ANC) < 500/uL (severe) or < 200/uL (very severe). Current ANC or last ANC prior to start of granulocyte colony-stimulating factor (G-CSF) may be used *** Platelets < 30,000/uL or transfusion dependence ***Absolute reticulocyte count < 40,000/uL ** Negative evaluation for inherited bone marrow failure conditions ** Must not meet diagnostic criteria for myelodysplastic syndrome defined in World Health Organization (WHO) 2008 consensus criteria * Must have refractory or relapsed disease, defined by persistent transfusion dependence and/or ANC < 500/uL at least 12 weeks after initiation of one course of immune suppression therapy
• Paroxysmal nocturnal hemoglobinuria * Patients must have testing (eg. flow cytometry demonstrating cells with absent CD55 or CD59 expression) demonstrating a paroxysmal nocturnal hemoglobinuria (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: ** Elevated lactate dehydrogenase (LDH) ** Low to absent serum haptoglobin ** Hemoglobinuria ** Reticulocytosis ** Studies demonstrating aberrant complement activation * 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 * To be eligible, patients must meet the following criteria: ** Must have evidence of bone marow (BM) failure, defined as a bone marrow biopsy demonstrating cellularity of < 25% in addition to peripheral blood cytopenias ** Must have chromosomal breakage (stress) testing performed demonstrating increased sensitivity to deoxyribonucleic acid (DNA) damage caused by mitomycin C (MMC) or diepoxybutane (DEB) ** Specific testing to define the subtype of Fanconi anemia through genetic sequencing for causative mutations or complementation group studies is strongly recommended, though not required
• Dyskeratosis congenita and related telomere disorders * To be eligible, patients must meet the following criteria: ** Must have evidence of BM failure, defined as a bone marrow biopsy demonstrating cellularity of < 25% in addition to peripheral blood cytopenias ** Must have lymphocyte telomere length analysis performed at a Clinical Laboratory Improvement Act (CLIA)-certified facility, demonstrating telomeres < 1%ile for age ** Specific gene sequencing testing to define the causative genetic mutation is strongly recommended, though not required
• Shwachman-Diamond syndrome * To be eligible, patients must meet the following criteria: ** Must have genetic testing confirming a mutation in the SBDS gene, and/or classic clinical features of Shwachman-Diamond syndrome, including pancreatic insufficiency, musculoskeletal anomalies, and endocrinopathies ** Must have developed trilineage BM failure, including BM cellularity < 25% * 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 * To be eligible, patients must meet the following criteria: ** Have a baseline ANC < 500/uL prior to G-CSF therapy ** Require chronic G-CSF therapy greater than 3 doses per week in order to maintain an ANC > 1000/uL ** 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 ** 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: * Includes, but not limited to: ** Diamond-Blackfan anemia (DBA) ** Congenital dyserythropoietic anemia (CDA) ** Congenital sideroblastic anemia (CSA) * Eligibility criteria include: ** Chronic red blood cell (RBC) transfusion dependence, with minimum frequency of every 8 weeks ** BM aspirate and biopsy demonstrating selective erythroid hypoplasia or dyserythropoiesis ** For patients with DBA, must have failed at least one therapeutic trial with corticosteroids ** Acquired viral and autoimmune causes of hypo-productive anemia have been excluded ** Specific genetic testing attempting to define the causative mutation is recommended but not required
• Congenital thrombocytopenia syndromes * Includes, but is not limited to, patients with congenital amegakaryocytic thrombocytopenia caused by mutations in the MPL gene * Eligibility criteria include: ** Platelet transfusion dependence with a minimum transfusion frequency of every 8 weeks ** Infectious, autoimmune, and other causes of secondary thrombocytopenia have been excluded ** Genetic sequencing of the MPL gene is required ** Additional genetic testing for causes of familial thrombocytopenia is recommended but not required
• Serum creatinine < 1.5 x upper limit of normal for age
• Transaminases =< 5 x upper limit of normal
• Bilirubin < 2.0 mg/dL, (unless elevation due to Gilberts disease or known hemolytic anemia)
• Shortening fraction >= 27%
• Diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% predicted in patients old enough to comply with pulmonary function tests (PFTs) or no baseline oxygen requirement for younger patients
• Lansky or Karnofsky performance >= 60
• 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 CMV, 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
• DONOR
• Donor selection will comply with 21 CFR 1271* of the U.S. Food and Drug Administration’s Code of Federal Regulations
• Unrelated donor meets National Marrow Donor Program criteria for donation
• For partially matched related donors, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone (CHOP) bone marrow transplant (BMT) standard procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases. Our donor collection program is Foundation for the Accreditation of Cellular Therapy (FACT) accredited
• For partially matched related donors, if subject has genetically confirmed inherited bone marrow failure (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 and also we review donor medical records and history 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

Exclusion Criteria

• 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