Chemotherapy, Total Body Irradiation, Donor Bone Marrow Transplant, and Immunosuppressive Therapy in Treating Patients with Severe Aplastic Anemia

Inclusion Criteria

• Confirmed diagnosis of SAA (acquired or inherited), either from initial diagnosis or follow-up assessments, defined as: * Bone marrow hypocellularity is required and relative to patient’s age (normocellularity is 100- patient age in years) ** Often marrow cellularity < 50% but with < 30% residual hematopoietic cells may be applied where appropriate at the discretion of the principal investigator (PI) * Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L, platelets < 20 x 10^9/L (without transfusions), reticulocyte count < 60 x 10^9/L
• No suitable fully matched related (6/6 match for human leukocyte antigen [HLA]-A and B at intermediate or high resolution and DRB1 at high resolution using deoxyribonucleic acid [DNA] based typing) donor if under age 25 years
• DONOR: * HLA haploidentical relative of the patient; a unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch; the donor and recipient must be identical at least one allele (high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 * If patient over age 25 years, may use HLA identical sibling donor * If patient has inherited bone marrow failure syndrome (IBMFS) and clear evidence of same disorder in potential related donors, unrelated donor may be used; unrelated donor must be a 10/10 match using HLA-A, -B, -C, DRB1, and DPB1; unrelated donor may also be used in case of donor specific antibodies to related donors or other clinical causes of unsuitable related donors
• Patient and/or legal guardian must sign informed consent for BMT
• The potential donor must be willing to donate bone marrow
• Left ventricular ejection fraction (LVEF) at rest >= 40%; for patients aged < 13 years, shortening fraction (SF) >= 26% by echocardiogram or LVEF by multigated acquisition scan (MUGA) may be used
• Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert’s disease are allowed to exceed this limit)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5.0 x ULN for age
• For patients >= 13.0 years of age at the time of enrollment: estimated creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
• For patients >= 1.0 year of age but < 13.0 years of age at the time of enrollment: glomerular filtration rate (GFR) estimated by the updated Schwartz formula >= 90 mL/min/1.73 m^2; if the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m^2
• For patients >= 8 years of age (or otherwise able to complete pulmonary function testing per established American Thoracic Society standards), diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced expiratory volume in one second (FEV1) > 50% predicted (without administration of bronchodilator) and forced volume vital capacity (FVC) > 50% predicted
• For patients < 8 years of age unable to perform pulmonary function tests (PFTs) due to age or developmental ability: (1) no evidence of dyspnea at rest and (2) no need for supplemental oxygen and (3) oxygen (O2) saturation > 92% on room air
• 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

• Patient with previous administration of immunosuppressive therapy for SAA
• Patients with Fanconi anemia; at a minimum, the diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow in patients younger than 30 years of age; (additional mutational testing may have been performed in a clinical or research capacity on a per patient basis but is not considered an exclusion criteria)
• Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. monosomy 7)
• Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, or DRB1 with mean fluorescence intensity [MFI] > 1000 by solid phase immunoassay)
• Prior allogeneic stem cell transplant
• Prior solid organ 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
• Seropositivity for the human immunodeficiency virus (HIV)
• Active hepatitis B or C determined by serology and/or nucleic acid testing (NAT)
• Female patients who are diagnosed as pregnant by beta human chorionic gonadotropin (hCG) testing (per institutional practice) or breast-feeding
• Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent > 5 years previously will be allowed; cancer treated with curative intent =< 5 years previously will not be allowed unless approved by the PI