Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures

Inclusion criteria

• Cohort A: Primary Immune Deficiencies with indication for HCT:
• Chronic granulomatous disease (CGD)
• Wiskott-Aldrich syndrome (WAS)
• Hyper-IgM syndrome
• Common variable immunodeficiency (CVID)
• Leukocyte adhesion deficiency-1 (LAD-1)
• Severe Combined Immunodeficiency (SCID)
• CTLA-4 deficiency
• CARD9 deficiency
• DOCK8 deficiency Immune Dysregulatory Syndromes:
• Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome
• Hemophagocytic lymphohistiocytosis (HLH) or related disorder with indication for transplant
• CAEBV: Patients with chronic EBV infection (CAEBV) with indication for BMT: Inherited Bone marrow failure disorders
• Congenital amegakaryocytic thrombocytopenia (CAMT)
• Diamond Blackfan anemia (DBA)
• Shwachman Diamond Syndrome (SDS)
• Thrombocytopenia Absent Radii (TAR)
• Glanzmans thrombasthenia (GT)
• Kostmann syndrome
• Other indications and/or other PID, IDS, and IBMFS diagnoses as deemed appropriate by the PI. Cohort B: Short telomere syndrome Cohort C: Confirmed diagnosis of Fanconi anemia or non-Fanconi DNA-dsb repair disorders
• Fanconi anemia
• Non-Fanconi DNA-dsb repair disorders
• Cerunnos-XRCC4-like factor deficiency (XLF or NHEJ1)
• DNA ligase IV deficiency (LIG4)
• Nijmegen breakage syndrome (NBS)
• Increased DNA breakage after exposure of patient cells to DNA cross-linking agents such as diepoxybutane or mitomycin C and germline mutation(s) in an identified Fanconi pathway gene. Available donor as follows:
• Fully HLA matched sibling or other first-degree family member.
• Fully HLA matched unrelated 10/10 donor using high-resolution DNA-based typing at the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1.
• Mismatched unrelated donor at 8 or 9/10 alleles, using high-resolution typing as above.
• HLA-haploidentical family members of any degree who match at least one allele of each of the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
• The patient and/or legal guardian must sign informed consent for BMT.
• Patients with adequate organ function as measured by
• Cardiac: Left ventricular ejection fraction (LVEF) at rest must be ≥ 35%. For patients aged \<13 years, shortening fraction (SF) \> 25% by echocardiogram or LVEF by MUGA may be used.
• Hepatic: Bilirubin ≤ 3.0 mg/dL; and ALT, AST, and Alkaline Phosphatase \< 5 x ULN.
• Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) \> 40 mL/min/1.73m2.
• Pulmonary: PFT with FEV1 and FVC \>/= 50% of normal and DLCO corrected for Hgb \>/= 40% of normal. Patients unable to undergo PFTs should have stable resp status with SaO2 \>90% on a max of 2L/min supplemental O2.
• Karnofsky or Lansky performance status ≥70%
• Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time, or agree to abstinence.

Exclusion criteria

• Patients will not be excluded on the basis of sex, racial or ethnic background.
• Positive leukocytotoxic crossmatch.
• Prior allogeneic stem cell transplant.
• Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment. The investigators recognize that patients with CAEBV may have ongoing EBV viremia at the time of initiating pre-transplant therapy, but other patients should have no uncontrolled bacterial, viral, or fungal infections.
• Diagnosis of idiopathic aplastic anemia
• Seropositivity for the human immunodeficiency virus (HIV)
• Active Hepatitis B or C determined by serology and/or NAT
• Female patients who are diagnosed as pregnant by beta bHCG testing (per institutional practice) or who are breast-feeding.
• Active malignancy or within the timeframe for significant concern for relapse of prior malignancy
• For Cohort B and C: liver biopsy (if performed, not required) with moderate-severe fibrosis/cirrhosis Donor Eligibility
• Donor must be medically, socially, and psychologically fit to donate
• Bone marrow is the preferred graft source, however, PBSCs may be requested. In particular, PBSCs may be preferred for patients with active viral reactivations and/or for patients who would benefit from a higher count in the graft. Cord blood is not permitted.
• First-degree relatives should be tested for degree of HLA match, CMV serology, ABO type, and complete blood count (CBC). An unrelated donor search should be initiated at the time the patient is referred for BMT.
• Age ≥5 years
• Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
• Lack of recipient anti-donor HLA antibody in recipient
• Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors.
• In inherited disorders, family members must be tested for carrier and disease status of the underlying disorders. In the event that family members are unaffected carriers, eligibility as donors will be decided upon by the PI on a case-by-case basis
• In the event that two or more eligible donors are identified, the donor will be selected per institutional standards. Suggested criteria include the following:
• Related is preferred over unrelated.
• The potential donor that is youngest in age is preferred.
• For CMV seronegative patients, a CMV seronegative donor is preferred. For CMV seropositive patients, a CMV seropositive donor is preferred.
• Red blood cell compatibility, in order of preference:
• RBC cross match compatible Minor ABO incompatibility, Major ABO incompatibility
• If the patient is male, male donors are preferred.