Overview

This is a phase II trial of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation in patients with inherited bone marrow failure (BMF) disorders to eliminate the need for routine graft-versus-host disease (GVHD) immune suppression leading to earlier immune recovery and potentially a reduction in the risk of severe infections after transplantation.

Eligibility

Patient Selection:

Inclusion Criteria:

For FA patients:

• Diagnosis of Fanconi anemia
  • Age <65 years of age
• Has one of the following risk factors:
  • Severe aplastic anemia (SAA)
  • Myelodysplastic features
  • High risk genotype
  • Immunodeficiency associated with history of recurrent infections
• Karnofsky performance status ≥ 70% if ≥ 16 years of age or Lansky play score ≥ 50%

  for patients <16 years of age

  • Adequate pulmonary, cardiac and liver function
  • Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care

For TBD patients:

• Diagnosis of TBD

• Age <70 years of age
• Has one of the following risk factors:
• Severe aplastic anemia (SAA)
• Myelodysplastic features
• Karnofsky performance status ≥ 70% if ≥ 16 years of age or Lansky play score

  ≥ 50% for patients <16 years of age

• Adequate pulmonary, cardiac and liver function
• Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care

Exclusion Criteria:

• Pregnant or breastfeeding as the treatment used in this study are Pregnancy Category D. Females of childbearing potential must have a negative pregnancy test (serum or urine) within 14 days of study registration
• Active, uncontrolled infection within 1 week prior to starting study therapy
• Malignant solid tumor cancer within previous 2 years

Donor Selection (Inclusion Criteria): meets one of the following match criteria:

• an HLA-A, B, DRB1 matched sibling donor (matched sibling)
• an HLA-A, B, DRB1 matched related donor (other than sibling)
• a related donor mismatched at 1 HLA-A, B, C and DRB1 antigen
• 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated donor per current institutional guidelines Patients and donors are typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing. If a donor has been selected on the basis of HLA-A, B, C and DRB1 typing as above, preference will be made for donors matched at the HLA-C locus.
• Body weight of at least 40 kilograms and at least 12 years of age
• Willing and able to undergo mobilized peripheral blood apheresis
• In general good health as determined by the medical provider
• Adequate organ function defined as:
  • Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)
  • Hepatic: ALT < 2 x upper limit of normal
  • Renal: serum creatinine < 1.8 mg/dl
• Performance of a donor infectious disease screen panel including CMV Antibody,

  Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV 1/2 Antibody, HTLVA 1/2 Antibody, Treponema, and Trypanosoma Cruzi (T. Cruzi) plus HBV, HCV, WNV, HIV by nucleic acid testing (NAT); and screening for evidence of and risks factors for infection with Zika virus, or per current standard institutional donor screen - must be negative for HIV and active hepatitis B

• Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start
• Voluntary written consent (parent/guardian and minor assent, if < 18 years) prior to the performance of any research related procedure