Inclusion Criteria: 

• Age 3 years to 75 years.
• Confirmed diagnosis of acquired SAA defined as:
  • Bone marrow cellularity < 25% or variable marrow cellularity but with < 30% residual hematopoietic cells deemed HYPOcellular for age AND;
  • Two (2) out of 3 of the following (in peripheral blood);
    • Neutrophils < 0.5 x109 /L ii. Platelets < 20 x109 /L
    • Reticulocyte count < 20 x109 /L (< 60 x 109 /L using an automated analysis)
• No suitable fully matched related donor as per Investigator’s discretion (6/6 match for HLA-A and B at intermediate or high-resolution and DRB1 at high-resolution using deoxyribonucleic acid [DNA]-based typing) available.
• Available donor per Section 2.4.
• Participant and/or legal guardian must sign informed consent.
• Adequate organ function defined by institutional transplant standards or defined as below:
  • Cardiac: Left ventricular ejection fraction (LVEF) at rest > 40% with no clinical signs of cardiac failure. For participants aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or multigated acquisition (MUGA) may be substituted for LVEF;
  • Hepatic: Total bilirubin < 2.0 mg/dL unless Gilbert’s disease is present;
  • Renal:
    • For participants > 13.0 years of age at the time of enrollment: estimated creatinine clearance (CrCl) > 60 mL/minute
    • For participants < 13.0 years of age at enrollment: glomerular filtration rate (GFR) estimated by the updated Schwartz formula1 ≥ 90 mL/min/1.73 m2 . If the estimated GFR is < 90 mL/min/1.73 m2 , then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m2 .
• Pulmonary:
  • For participants > 13.0 years of age:
    • Diffusing capacity of the lung for carbon monoxide (DLCO, corrected/adjusted for hemoglobin [Hb]) > 50%;
    • Spirometry with forced expiratory volume 1 (FEV1) > 50% predicted (without administration of bronchodilator) and forced vital capacity (FVC) > 50% predicted.
  • For participants < 13.0 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) O2 saturation > 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care [e.g., Utah, 4,200 feet above sea level, does not give supplemental oxygen unless below 90%]).
• Karnofsky or Lansky performance status ≥ 60%.
• 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: 

• Inherited bone marrow failure syndromes such as Fanconi anemia and short telomere syndromes must be ruled out according to center standards. It is recommended that functional testing for Fanconi Anemia (di-epoxybutane [DEB] chromosomal breakage analysis) and telomere length assessment be performed. If available, genetic panels for inherited bone marrow failure syndromes can be considered as an alternative to functional testing.
• Clonal cytogenetic abnormalities consistent with pre-MDS or MDS on marrow examination (e.g., monosomy 7 and other MDS-defining changes per recent pathology guidelines).[42, 43]
• Formal diagnosis of MDS by World Health Organization (WHO) 2022 or International Consensus Classification (ICC).[42, 43]
• Recipient positive for HLA antibodies against a mismatched HLA in the selected donor determined by the presence of donor specific HLA antibodies (DSA) to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, –DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 by microarray-based single antigen bead testing. In patients receiving red blood cell or platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and immediately prior to initiation of recipient preparative regimen to ensure there is confirmation of no DSA to the selected donor when conditioning starts.
• Prior desensitization attempt for HLA antibodies to chosen donor. Any intervention with the sole intent to reduce the level of HLA DSA, (e.g., plasmapheresis, intravenous immunoglobulin [IVIG], MMF, etc.) would constitute a desensitization attempt.
• Prior treatment for SAA (e.g., immunosuppressive therapy using ATG, calcineurin inhibitors [CNIs], thrombopoietin receptor agonists or androgens). Short courses of steroids or IVIG that were not explicitly administered for SAA therapy will be allowed.
• Prior allogeneic stem cell transplant.
• Prior solid organ transplant.
• Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® (Sanofi) that would prohibit use for the participant as this study requires use of the Thymoglobulin® (Sanofi) preparation of ATG.
• 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.
• Female participants who are pregnant, as detected using a pregnancy test as 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 Protocol Chairs and/or Protocol Officer.

Of note, participants with seropositivity for the human immunodeficiency virus (HIV) may be considered if viral load is undetectable. Similarly, carriers of hepatitis B (HepB) or hepatitis C (HepC) may not have a detectable viral load of HepB virus or HepC virus. Participants with HIV that is well-controlled on combination antiretroviral therapy and no AIDS-related complications within the past 12 months are eligible.

Infections other than HIV:

• Prior infections must be controlled;
• HepB participants are eligible if on effective suppressive therapy and otherwise meet inclusion/exclusion criteria;
• HepC participants are eligible if otherwise meet inclusion/exclusion criteria.

Donor Selection Criteria

• Donor selection is based on HLA typing and relationship to recipient.
• When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen unless there is HLA incompatibility due to HLA antibodies or a medical reason. In cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of HLA compatibility and ABO compatibility. Prioritization is given to the lowest number of mismatches in the Host Versus Graft (HVG) direction to minimize the risk of graft failure.
• All Donors must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 and recommend -DQA1 and DPA1 for cases with possible participant –DQA1 or DPA1 anti-HLA antibodies.
  • For URDs, must be unrelated to the participant and high-resolution HLA-matched at 8/10, 9/10, or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1) with up to one mismatch allowed at HLA-A, -B, -C, or -DRB1;
  • For Haplo Donors, available relative of the patient who is a haploidentical match, including biological parents, siblings or half siblings, children, uncles/aunts, first cousins, etc. Eligible haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1 typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must demonstrate that they are a full haplotype match by being identical at a minimum of one allele (at high-resolution DNA based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, - C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local center.
• Age > 18 years at the time of signing informed consent.
• Meet the medical suitability requirements of donor registries’ (unrelated) or individual sites’ (haploidentical) for bone marrow (BM) donation.
• Must undergo eligibility screening according to current Food and Drug Administration (FDA) requirements. Donors who do not meet one or more of the donor screening requirements may donate under urgent medical need.
• Must agree to donate BM.
• Additional considerations for donor selection should be given to:
  • Prioritize donors under 35 years of age but depends on clinical situation, e.g., BM and size of donor;
  • Avoid donors where the estimated cell dose (total nucleated cells [TNC]) will be <2.5x108 /kg recipient weight. Cell dose can be estimated using the following NMDP formula:[45] Estimated maximum donor volume2 x 0.183e8/mL = Estimated total nucleated cells;
  • ABO compatibility;
  • CMV matching
  • ;B-Leader genotype for HLA-B mismatched donor;
  • Male over female for larger donor weight or donor weight if known;
  • Domestic donors over international donors for speed of acquisition.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 7/11/2024. Questions regarding updates should be directed to the study team contact.