• Overall survival [ Time Frame: At 1 year post-transplant ]
• Event-free survival [ Time Frame: At 1 year post-transplant ]
  Defined as death due to any cause, donor lymphocyte infusion, CD34 boost, second transplant, graft rejection or graft failure, or the development of myelodysplastic syndrome or leukemia following transplant (whichever event occurs first).
• Transplant-related mortality [ Time Frame: At day 100 after transplant ]
• Incidence of grade II-IV acute graft-versus-host disease [ Time Frame: At day 100 ]
• Incidence of chronic graft-versus-host disease [ Time Frame: At 1 year after transplant ]
• Donor chimerism CD3 & CD33 [ Time Frame: At 1 year after transplant ]

OUTLINE:

Patients receive thiotepa intravenously (IV) twice daily (BID) on day -7, treosulfan IV on days -6 to -4, fludarabine phosphate IV on days -6 to -2, and rabbit anti-thymocyte globulin IV on days -4 to -2. Patients then undergo allogeneic hematopoietic cell transplant via infusion on day 0.

After completion of study treatment, patients are followed up at 1 year and then annually thereafter.

• Drug: Thiotepa
  Given IV
  Other Names:

  • 1,1',1"-phosphinothioylidynetrisaziridine
  • N,N', N''-Triethylenethiophosphoramid
  • Oncotiotepa
  • STEPA
  • Tepadina
  • TESPA
  • Tespamin
  • Tespamine
  • Thio-Tepa
  • Thiofosfamide
  • Thiofozil
  • Thiophosphamide
  • Thiophosphoramide
  • Thiotef
  • Tifosyl
  • TIO TEF
  • Triethylene thiophosphoramide
  • Triethylenethiophosphoramide
  • TSPA
• Drug: Treosulfan
  Given IV
  Other Names:

  • (S-(R*,R*))-1,2,3,4-butanetetrol
  • 1,4-dimethanesulfonate
  • [R-(R*,S*)]-, 299-75-2, 39069
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon
• Drug: Fludarabine Phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • 312887
  • 328002
  • 75607-67-9
  • 9H-Purin-6-amine
  • 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Fludarabine-5'-Monophosphate
• Biological: Rabbit Anti-Thymocyte Globulin
  Given IV
• Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
  Undergo HCT via infusion
  Other Names:

  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Inclusion Criteria:

• Patient with nonmalignant disease treatable by allogenic HCT
• Patient with a nonmalignant disease that is not clearly defined (a patient with a non-malignant disease HCT for whom a genetic mutation responsible for their non-malignant disease phenotype has not been identified) are eligible for the study following discussion with and approval by the protocol principal investigator (PI) (Dr. Lauri Burroughs)
• DONOR: For the very few occasions where we identify a donor hematopoietic progenitor cell (HPC)-A from a non-NMDP source, we have procedures in place through our unrelated donor office to collect the information necessary to comply with donor testing, screening, and declaration of donor eligibility according to 21 Code of Federal Regulations (CFR) 1271. We require that the donor testing be performed by a United States Clinical Laboratory Improvement Amendment (CLIA) approved laboratory. In the very rare case where the donor testing is not able to be performed in a CLIA-approved laboratory, or there is confirmatory testing that needs to be performed, or for any donor identified from Europe and at risk for Creutzfeldt-Jakob disease (CJD), we note this on the donor screening form and require that the unrelated donor medical director or the attending physician approves the use of the donor HPC-A product under urgent medical need
• DONOR: Human leukocyte antigen (HLA)-identical related donor OR unrelated donor matched for HLA-A, B, C, DRB1 and DQB1 or mismatched for a single allele at HLA-A, B, C, or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing

• DONOR: Bone marrow is the preferred cell source (when feasible). However, peripheral blood stem cells (PBSC) is also allowed and the PI may determine if PBSC is preferred for certain patients

  • The recommended total nucleated cell count (TNC) for bone marrow grafts is >= 4.0 x 10^8 TNC/kg (actual recipient weight)
  • The recommended CD34 cell count for PBSC grafts is >= 5 x 10^6 CD34/kg (actual recipient weight) and the recommended maximum CD34 cell count for PBSC grafts is 10 x 10^6 CD34/kg (actual recipient weight)
• DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and stored. The HLA-matched sibling bone marrow and cord blood would be matched for HLA-A, B, C, DRB1 and DQB1

Exclusion Criteria:

• Patients with idiopathic aplastic anemia and Fanconi anemia; patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria (PNH) or inherited marrow failure syndromes (except Fanconi anemia) will be allowed
• Impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction of < 26% may be enrolled if approved by a cardiologist
• Impaired pulmonary function as evidenced by carbon monoxide diffusing capability (DLCO) < 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen [O2] saturation < 92% on room air)

• Impaired renal function as evidenced by:

  • Estimated creatinine clearance < 60 mL/min/1.73m^2 using either the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation for adult patients (> 18 years old), or the updated Schwartz formula for pediatric patients (< 18 years old). If the estimated creatinine clearance is < 60 mL/min/1.73m^2, then renal function must be measured by 24-hour creatinine clearance, Iothalamate, Iohexol or nuclear GFR and the patient is excluded if their measured creatinine clearance is < 50 mL/min/1.73 m^2, OR
  • Serum creatinine > 2 x upper limit of normal, OR
  • Dialysis dependent
• Evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist
• Active infectious disease requiring deferral of conditioning as recommended by an infectious disease specialist
• Positive for HIV (human immunodeficiency virus)
• Females who are pregnant or breast-feeding
• Known hypersensitivity to treosulfan, fludarabine, and/or thiotepa
• DONOR: Donors deemed unable to undergo marrow harvesting of PBSC mobilization and leukapheresis
• DONOR: HIV-positive donors
• DONOR: Donors with active infectious hepatitis
• DONOR: Female donor with positive pregnancy test
• DONOR: Donors are excluded if the patient has an identified antibody against a donor-specific HLA locus as specified in standard practice
• DONOR: HLA-matched sibling cord blood units that have not passed donor screening for infectious disease markers as recommended by the National Marrow Donor Project (NMDP) will not be used unless a waiver is signed by the clinical attending allowing use of cord blood unit. Cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies

• National Cancer Institute (NCI)
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)