TCRalpha/beta and CD19+ depleted Hematopoietic Stem Cell Transplant from Closely Matched Unrelated Donors or Haploidentical Related donors for Blood Disorders in Children and Young Adults

Inclusion Criteria

• Patients must be 3 months =< 40 years of age with the exception of patients with sickle cell disease and thalassemia, who must be =< 21 years of age
• Sickle cell disease or thalassemia (Hemoglobin SS, Sbeta0-thalassemia) complicated by any of the following: * Recurrent acute painful episodes (also known as vaso-occlusive crises; VOC) despite supportive care, minimum of 2 new pain events per year requiring hospitalization for parenteral pain management in the previous 2 years * Recurrent acute chest syndrome (ACS) despite supportive care, minimum of 2 episodes in preceding 2-year period * Stroke or neurologic event lasting > 24 hours with an accompanying infarct on magnetic resonance imaging (MRI) in any patient for all ages; Brain MRI with silent infarct without clinical event in patients =< 16 years * Chronic transfusion therapy defined as > 8 packed red blood cell transfusions per year in the year prior to enrollment and/or evidence of red blood cell alloimmunization * Elevated transcranial Doppler velocities - > 200 cm/s, via the non-imaging technique or > 185 cm/s by the imaging technique measured on 2 separate occasions >= 1-month apart * Elevated tricuspid valve regurgitation velocity (TRV) > 2.6m/s in patients >= 16 years old * Sickle-related renal insufficiency and/or sickle hepatopathy and/or any irreversible end-organ damage in patients >= 16 years old * Hydroxyurea must have been trialed for at least six months, and failed, in patients with sickle cell disease
• Beta-thalassemia complicated by transfusion dependence with evidence of iron overload
• Paroxysmal nocturnal hemoglobinuria with bone marrow failure (< 25% bone marrow cellularity) * Patients must have testing (e.g., flow cytometry demonstrating cells with absent CD55 or C59 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 measurement (LDH) * Low to absent serum haptoglobin * Hemoglobinuria * Reticulocytosis * Studies demonstrating aberrant complement activation Myelodysplastic Syndromes-Lower Risk * Primary or secondary (except for chemotherapy and/or radiation therapy [XRT] induced) * Not transformed to leukemia * Absence of monosomy 7 (-7, 7q-, der(1;7)) * Blasts < 20%
• Fanconi anemia * To be eligible, patients must meet the following criteria: ** Must have evidence of bone marrow (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, although not required
• Diamond blackfan anemia (DBA) ▪ 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 ** Abnormal red cell adenosine (eADE) level ** 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
• Dyskeratosis congenita and related telomere disorders * To be eligible, patient 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 < one percentile for age in lymphocyte subsets ** Specific gene sequencing testing to define the causative genetic mutation is strongly recommended, although not required
• Congenital thrombocytopenia syndromes (including, but not limited to, 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
• Severe congenital neutropenia (SCN) * To be eligible, patients must meet the following criteria: ** Have a baseline absolute neutrophil count (ANC) < 500/uL prior to granulocyte colony-stimulating factor (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
• Shwachman-Diamond Syndrome * To be eligible, patients must meet the following criteria: ** Must have genetic testing confirming a mutation in the Shwachman-Diamond Syndrome (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 must have a performance status of Karnofsky >= 60 for patients > 16 years of age and Lansky >= 60 for patients =< 16 years of age
• Patients must have a life expectancy of >= 3 months
• Patient must have fully recovered from the acute toxic effects of all prior therapies (e.g. chemotherapy where indicated) prior to entering this study
• All patients must have adequate renal function defined as serum creatinine < 1.5 x upper limit or normal for age and glomerular filtration rate (GFR) of at least 60 ml/min/1.73m^2
• Total bilirubin < 2 mg/dL (unless elevation is due to Gilberts disease or known hemolytic anemia)
• Transaminases =< 3 x upper limit of normal for age
• All patients must have adequate cardiac function defined as a shortening fraction of >= 27% and ejection fraction of at least 40% by multigated acquisition scan (MUGA) or echocardiogram
• No baseline supplemental oxygen requirement
• If measured, carbon monoxide diffusion capacity (DLCO) > 50%
• No serious, uncontrolled, active infection at screening
• 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 antifungal 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
• Either haploidentical or closely HLA-matched unrelated donor available who is willing to undergo mobilization and apheresis * The above alternative donors may be used without searching for a suitable HLA matched unrelated donor if the urgent need of HSCT precludes the time necessary for the NMDP search * If subject has genetically confirmed inherited PID, or bone marrow failure syndrome, or myelodysplastic syndrome (MDS), a related donor must be evaluated for this disorder and testing must be negative * If subject has sickle cell disease, a related donor may have only sickle cell trait
• Patient (if >= 18 years of age) or legal guardian must provide written informed consent
• DONORS: Donor eligibility will be determined in compliance with Code of Federal Regulations 21 CFR 1271, subpart C. For a donor to be eligible, the donor must meet donor criteria for human cells, tissues and cellular and tissue based products. Specifically, a donor is eligible under these provisions only if: * Donor screening in accordance with 1271.75 indicates that the donor: ** Is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases; and ** Is free from communicable disease risks associated with xenotransplantation; and * The results of donor testing for relevant communicable disease agents in accordance with 1271.80 and 1271.85 are negative or nonreactive, except as provided in 1271.80(d)(1). In compliance with CFR1271.85(b) * An institutional standard operating procedure (SOP) governs the release of donor cells whose specimen tests reactive for CMV. If a donor does not meet these criteria, he/she is not eligible
• CLOSE MATCHED UNRELATED DONORS: Donors must meet the National Marrow Donor Program criteria for donation (NCT00785525)
• CLOSELY MATCHED UNRELATED DONORS: Donors must be an antigen and allele match at >= 8/10 HLA loci
• CLOSELY MATCHED UNRELATED DONORS: In a donor with 2 mismatches, only one mismatch involving HLA-A, -B, or DRB1 will be allowed
• CLOSELY MATCHED UNRELATED DONORS: When more than one, otherwise equal, donor options is available, donor preference will be based on consideration of donor and recipient CMV and EBV serostatus and ABO compatibility
• HAPLOIDENTICAL DONORS: For haploidentical donors, the University of Wisconsin Hospital Clinical Hematopoietic Cell Processing Laboratory (UWCHCPL) standard operating procedures (SOP) apply for purposes of determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases. Our program holds accreditation by the Foundation for Accreditation of Cellular Therapy (FACT)
• HAPLOIDENTICAL DONORS: Infectious disease testing of donors will be performed per current UWCHCPL SOPs, which comply with 21 CFR 1271. Laboratory testing of infectious disease will be performed at the time of initial donor assessment and must be performed within 30 days of the HSC collection. If multiple collections of HSC occur from the same donor, the infectious disease testing shall be performed within 30 days prior to each collection
• HAPLOIDENTICAL DONORS: High resolution HLA typing at HLA-A, -B, -C, DRB1, and DQB1 loci and intermediate resolution typing at DPB1 will be performed on all potential donors and matching must be >= 5/10 but < 10/10 HLA match
• HAPLOIDENTICAL DONORS: When more than one, otherwise equal, donor options is available, donor preference will be based on consideration of donor and recipient CMV and EBV serostatus and ABO compatibility. If the patient is being transplanted for Chronic Granulomatous Disease using a haploidentical donor, the maternal donor should be used in autosomal recessive disease and the paternal or non-X-CGD carrier donor should be used in X-linked disease
• HAPLOIDENTICAL DONORS: Haploidentical donor willing to undergo G-CSF mobilization and stem cell apheresis
• HAPLOIDENTICAL DONORS: The donor must be in good general health as determined by the evaluating medical provider using the University of Wisconsin (UW) Hematopoietic Stem Cell Transplant Program guidelines set forth in the most current standard operating policies and procedures for hematopoietic donor evaluation and selection.
• HAPLOIDENTICAL DONORS: Donors with limited or no literacy and those who cannot read or speak English are eligible. However, additional consent processes must be followed as described by the the current policy and guidance of the UW Health Sciences Institutional Review Boards
• HAPLOIDENTICAL DONORS: Haploidentical donors must be aged 18-60 years

Exclusion Criteria

• HLA matched sibling donor or HLA matched unrelated donor available
• Positive pregnancy test
• Human immunodeficiency virus (HIV) infection
• Any other ongoing serious medical problem, or its treatment, unrelated to the indication for HSCT that is not covered by the exclusion criteria and which is expected to significantly increase the risk of transplantation or adversely affect survival (for example, but not limited to, major congenital anomalies such as central nervous system (CNS) malformations, urea cycle disorders, intractable seizures)
• Enrollment in any other treatment study, that according to the judgement of the principal investigator (PI) (or PI designee) would interfere with the endpoints of this study, is not allowed. Participation in NCT03798301 will be allowed, a phase I study treating patients with treatment-refractory CMV infection using viral specific T cells obtained from the donor. Those treatment studies that are permitted will be clearly documented in the case report form (CRF) and in the patient’s medical file
• DONORS: Female donors who are of reproductive potential must have a negative pregnancy test. The pregnancy test must be repeated if more than 7 days transpire from the date of the negative pregnancy test to the date of initiation of patient conditioning regimen. The repeat test, if performed, must be negative